Hetero-halo inhibitors of histone deacetylase

ABSTRACT

This invention provides compounds that are inhibitors of HDAC2. The compounds (e.g., compounds according to Formula I, II or any of Compounds 100-128 or any of those in Tables 2 or 3) accordingly are useful for treating, alleviating, or preventing a condition in a subject such as a neurological disorder, memory or cognitive function disorder or impairment, extinction learning disorder, fungal disease or infection, inflammatory disease, hematological disease, or neoplastic disease, or for improving memory or treating, alleviating, or preventing memory loss or impairment.

REFERENCE TO RELATED APPLICATIONS

This application is continuation of a U.S. application Ser. No.15/741,657, filed Jan. 3, 2018, which is a § 371 national stage filingof International Application No. PCT/US2016/040957, filed Jul. 5, 2016,which claims the benefit of U.S. Provisional Application No. 62/188,857,filed Jul. 6, 2015, the entire contents of each of which areincorporated herein by reference.

This invention was made with government support under Small BusinessInnovation Research (SBIR) grant 1R43AG048651-01A1 awarded by theNational Institute of Health (NIH). The government has certain rights inthe invention.

BACKGROUND OF THE INVENTION

Inhibitors of histone deacetylases (HDAC) have been shown to modulatetranscription and to induce cell growth arrest, differentiation andapoptosis. HDAC inhibitors also enhance the cytotoxic effects oftherapeutic agents used in cancer treatment, including radiation andchemotherapeutic drugs. Marks, P., Rifkind, R. A., Richon, V. M.,Breslow, R., Miller, T., Kelly, W. K. Histone deacetylases and cancer:causes and therapies. Nat Rev Cancer, 1, 194-202, (2001); and Marks, P.A., Richon, V. M., Miller, T., Kelly, W. K. Histone deacetylaseinhibitors. Adv Cancer Res, 91, 137-168, (2004). Moreover, recentevidence indicates that transcriptional dysregulation may contribute tothe molecular pathogenesis of certain neurodegenerative disorders, suchas Huntington's disease, spinal muscular atrophy, amyotropic lateralsclerosis, and ischemia. Langley, B., Gensert, J. M., Beal, M. F.,Ratan, R. R. Remodeling chromatin and stress resistance in the centralnervous system: histone deacetylase inhibitors as novel and broadlyeffective neuroprotective agents. Curr Drug Targets CNS Neurol Disord,4, 41-50, (2005). A recent review has summarized the evidence thataberrant histone acetyltransferase (HAT) and histone deacetylases (HDAC)activity may represent a common underlying mechanism contributing toneurodegeneration. Moreover, using a mouse model of depression, Nestlerhas recently highlighted the therapeutic potential of histonedeacetylation inhibitors (HDAC5) in depression. Tsankova, N. M., Berton,O., Renthal, W., Kumar, A., Neve, R. L., Nestler, E. J. Sustainedhippocampal chromatin regulation in a mouse model of depression andantidepressant action. Nat Neurosci, 9, 519-525, (2006).

There are 18 known human histone deacetylases, grouped into four classesbased on the structure of their accessory domains. Class I includesHDAC1, HDAC2, HDAC3, and HDAC8 and has homology to yeast RPD3. HDAC4,HDAC5, HDAC7, and HDAC9 belong to class IIa and have homology to yeast.HDAC6 and HDAC10 contain two catalytic sites and are classified as classIIb. Class III (the sirtuins) includes SIRT1, SIRT2, SIRT3, SIRT4,SIRT5, SIRT6, and SIRT7. HDAC11 is another recently identified member ofthe HDAC family and has conserved residues in its catalytic center thatare shared by both class I and class II deacetylases and is sometimesplaced in class IV.

In contrast, HDACs have been shown to be powerful negative regulators oflong-term memory processes. Nonspecific HDAC inhibitors enhance synapticplasticity as well as long-term memory (Levenson et al., 2004, J. Biol.Chem. 279:40545-40559; Lattal et al., 2007, Behav Neurosci121:1125-1131; Vecsey et al., 2007, J. Neurosci 27:6128; Bredy, 2008,Learn Mem 15:460-467; Guan et al., 2009, Nature 459:55-60; Malvaez etal., 2010, Biol. Psychiatry 67:36-43; Roozendaal et al., 2010, J.Neurosci. 30:5037-5046). For example, HDAC inhibition can transform alearning event that does not lead to long-term memory into a learningevent that does result in significant long-term memory (Stefanko et al.,2009, Proc. Natl. Acad. Sci. USA 106:9447-9452). Furthermore, HDACinhibition can also generate a form of long-term memory that persistsbeyond the point at which normal memory fails. HDAC inhibitors have beenshown to ameliorate cognitive deficits in genetic models of Alzheimer'sdisease (Fischer et al., 2007, Nature 447:178-182; Kilgore et al., 2010,Neuropsychopharmacology 35:870-880). These demonstrations suggest thatmodulating memory via HDAC inhibition have considerable therapeuticpotential for many memory and cognitive disorders.

Currently, the role of individual HDACs in long-term memory has beenexplored in two recent studies. Kilgore et al. 2010,Neuropsychopharmacology 35:870-880 revealed that nonspecific HDACinhibitors, such as sodium butyrate, inhibit class I HDACs (HDAC1,HDAC2, HDAC3, HDAC8) with little effect on the class IIa HDAC familymembers (HDAC4, HDAC5, HDAC7, HDAC9). This suggests that inhibition ofclass I HDACs may be critical for the enhancement of cognition observedin many studies. Indeed, forebrain and neuron specific over expressionof HDAC2, but not HDAC1, decreased dendritic spine density, synapticdensity, synaptic plasticity and memory formation. (Guan et al., 2009,Nature, 459:55-60). In contrast, HDAC2 knockout mice exhibited increasedsynaptic density, increased synaptic plasticity and increased dendriticdensity in neurons. These HDAC2 deficient mice also exhibited enhancedlearning and memory in a battery of learning behavioral paradigms. Thiswork demonstrates that HDAC2 is a key regulator of synaptogenesis andsynaptic plasticity. Additionally, Guan et al. showed that chronictreatment of mice with SAHA (an HDAC 1, 2, 3, 6, 8 inhibitor) reproducedthe effects seen in the HDAC2 deficient mice and recused the cognitiveimpairment in the HDAC2 overexpression mice.

Accordingly, the inhibition of the HDAC2 (selectively or in combinationwith inhibition of other class I HDACs) is an attractive therapeutictarget. Such inhibition has the potential for enhancing cognition andfacilitating the learning process through increasing synaptic anddendritic density in neuronal cell populations. In addition, inhibitionof HDAC2 may also be therapeutically useful in treating a wide varietyof other diseases and disorders.

DETAILED DESCRIPTION OF THE INVENTION 1. General Description of CertainEmbodiments of the Invention

This invention provides compounds that are inhibitors of HDAC2. Thecompounds accordingly are useful for treating, alleviating, orpreventing a condition in a subject such as a neurological disorder,memory or cognitive function disorder or impairment, extinction learningdisorder, fungal disease or infection, inflammatory disease,hematological disease, or neoplastic disease, or for improving memory ortreating, alleviating, or preventing memory loss or impairment.

In some embodiments the present invention provides a compound of formulaI:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is selected from

R¹ is an optionally substituted monocyclic or bicyclic, non-aromaticheterocyclyl;

R² is selected from optionally substituted C₂-C₆ alkenyl, optionallysubstituted heteroaryl, optionally substituted partially unsaturatedheterocyclyl, optionally substituted partially unsaturated carbocyclyl,and para-substituted phenyl wherein said phenyl can be optionallyfurther substituted, and when ring A comprises two nitrogen atoms, R² isadditionally selected from unsubstituted phenyl,

wherein any two substituents on adjacent ring atoms in R² are optionallytaken together with the adjacent ring atoms to form a ring that is anaryl, a carbocyclyl, a heteroaryl, or a heterocyclyl ring;

R³, when present, is selected from chloro, fluoro, —CF₃ and —CHF₂;

n is 0 or 1;

“1” represents a point of attachment between ring A and —NH—C(O)—R¹;

“2” represents a point of attachment between ring A and R²;

“3” represents a point of attachment between ring A and —NH₂.

In one embodiment, R² in the compounds of formula I is selected fromoptionally substituted C₂-C₆ alkenyl, optionally substituted heteroaryl,optionally substituted partially unsaturated heterocyclyl, optionallysubstituted partially unsaturated carbocyclyl, and para-substitutedphenyl, and when ring A comprises two nitrogen atoms, R² is additionallyselected from unsubstituted phenyl,

wherein any two substituents on adjacent ring atoms in R² are optionallytaken together with the adjacent ring atoms to form a ring that is anaryl, a carbocyclyl, a heteroaryl, or a heterocyclyl ring;

In other embodiments the present invention provides a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein

ring A′B′ is a fused bicyclic ring system containing at least twonitrogen atoms, wherein ring A′ is a 6-membered heterocyclyl and ring B′is a 5-membered heteroaryl;

X¹ is carbon or nitrogen;

R^(3′) and R⁴ are each independently halo, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, or halo(C₁-C₄)alkoxy;

R⁵ is halo, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,monocyclic heterocyclyl, or (C₁-C₄)alkyl optionally substituted withmonocyclic heterocyclyl, wherein each of said heterocyclyl areoptionally and independently substituted with 1 to 2 groups selectedfrom halo, (C₁-C₄)alkyl, and halo(C₁-C₄)alkyl;

n′ is 0 or 1; and

p and t are each independently 0, 1, or 2.

2. Compounds and Definitions

Compounds of this invention include those described generally forformula I and II, above, and are further illustrated by the classes,subclasses, and species disclosed herein. It will be appreciated thatpreferred subsets described for each variable herein can be used for anyof the structural subsets as well. As used herein, the followingdefinitions shall apply unless otherwise indicated.

As described herein, compounds of the invention may be optionallysubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, means that a hydrogenradical of the designated moiety is replaced with the radical of aspecified substituent, provided that the substitution results in astable or chemically feasible compound. The term “substitutable”, whenused in reference to a designated atom, means that attached to the atomis a hydrogen radical, which hydrogen atom can be replaced with theradical of a suitable substituent. Unless otherwise indicated, an“optionally substituted” group may have a substituent at eachsubstitutable position of the group, and when more than one position inany given structure may be substituted with more than one substituentselected from a specified group, the substituent may be either the sameor different at every position. Combinations of substituents envisionedby this invention are preferably those that result in the formation ofstable or chemically feasible compounds.

A stable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature from about −80° C. to about +40° C., in the absence ofmoisture or other chemically reactive conditions, for at least a week,or a compound which maintains its integrity long enough to be useful fortherapeutic or prophylactic administration to a patient.

The phrase “one or more substituents”, as used herein, refers to anumber of substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites,provided that the above conditions of stability and chemical feasibilityare met.

As used herein, the term “independently selected” means that the same ordifferent values may be selected for multiple instances of a givenvariable in a single compound.

As used herein, the term “aromatic” includes aryl and heteroaryl groupsas described generally below and herein.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain or branched C₁₋₁₂ hydrocarbon which is completelysaturated or which contains one or more units of unsaturation. Forexample, suitable aliphatic groups include linear or branched alkyl,alkenyl, alkynyl, alkylene, alkenylene, and alkynylene groups. Unlessotherwise specified, in various embodiments, aliphatic groups have 1-12,1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms. Aliphatic groups can beunsubstituted or substituted (e.g., having 1, 2, 3, or 4 substituentgroups as defined herein).

The term “alkenyl”, used alone or as part of a larger moiety, refers toan optionally substituted straight or branched chain hydrocarbon grouphaving at least one double bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or2-3 carbon atoms.

The terms “cycloaliphatic”, “carbocycle”, “carbocyclyl”, “carbocyclo”,or “carbocyclic”, used alone or as part of a larger moiety, refer to anoptionally substituted saturated or partially unsaturated cyclicaliphatic ring system having from 3 to about 14 ring carbon atoms, andwhich is not aromatic. In some embodiments, the cycloaliphatic group isan optionally substituted monocyclic hydrocarbon having 3-8 or 3-6 ringcarbon atoms. Cycloaliphatic groups include, without limitation,optionally substituted cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl,cyclooctyl, cyclooctenyl, or cyclooctadienyl. The terms“cycloaliphatic”, “carbocycle”, “carbocyclyl”, “carbocyclo”, or“carbocyclic” also include optionally substituted bridged or fusedbicyclic rings having 6-12, 6-10, or 6-8 ring carbon atoms, wherein anyindividual ring in the bicyclic system has 3-8 ring carbon atoms.

As used herein, the term “halogen” or “halo” means F, Cl, Br, or I.

The terms “aryl” and “ar-”, used alone or as part of a larger moiety,e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to an optionallysubstituted C₆-14 aromatic hydrocarbon moiety comprising one to threearomatic rings. Preferably, the aryl group is a C₆₋₁₀ aryl group. Arylgroups include, without limitation, optionally substituted phenyl,naphthyl, or anthracenyl. The terms “aryl” and “ar-”, as used herein,also include groups in which an aryl ring is fused to one or morecycloaliphatic rings to form an optionally substituted cyclic structuresuch as a tetrahydronaphthyl, indenyl, or indanyl ring. The term “aryl”may be used interchangeably with the terms “aryl group”, “aryl ring”,and “aromatic ring”.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms;having 6, 10, or 14 it electrons shared in a cyclic array; and having,in addition to carbon atoms, from one to five heteroatoms. A heteroarylgroup may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, ortricyclic, more preferably mono- or bicyclic, as long as each ring isaromatic. The term “heteroatom” refers to nitrogen, oxygen, or sulfur,and includes any oxidized form of nitrogen or sulfur, and anyquaternized form of a basic nitrogen. For example, a nitrogen atom of aheteroaryl may be a basic nitrogen atom and may also be optionallyoxidized to the corresponding N-oxide. When a heteroaryl is substitutedby a hydroxy group, it also includes its corresponding tautomer. Theterms “heteroaryl” and “heteroar-”, as used herein, also include groupsin which a heteroaromatic ring is fused to one or more aryl,cycloaliphatic, and/or heterocyclic rings. Nonlimiting examples ofheteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl,pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl,dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[2,3-b]-1,4-oxazin-3(4H)-one. The term “heteroaryl” may be usedinterchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or“heteroaromatic”, any of which terms include rings that are optionallysubstituted. The term “heteroaralkyl” refers to an alkyl groupsubstituted by a heteroaryl, wherein the alkyl and heteroaryl portionsindependently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 3- to 8-membered monocyclic or 7-10-membered bicyclic moietythat is either saturated or partially unsaturated in at least one ring,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above.

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl.Unless otherwise specified, a heterocyclyl group may be mono-, bi-,tri-, or polycyclic, preferably mono-, bi-, or tricyclic, morepreferably mono- or bicyclic. Additionally, a heterocyclic ring alsoincludes groups in which the heterocyclic ring is fused to one or morearyl, heteroaryl and/or carbocyclic rings.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms. Theterm “partially unsaturated” is intended to encompass rings havingmultiple sites of unsaturation, but is not intended to include aromatic(e.g., aryl or heteroaryl) moieties, as herein defined.

An aryl or heteroaryl group may contain one or more substituents (e.g.,1, 2, 3, or 4 substituents) and thus may be “optionally substituted”. Inaddition to the substituents defined above and herein, suitablesubstituents on the unsaturated carbon atom of an aryl or heteroarylgroup also include and are generally selected from -halo, —NO₂, —CN,—R⁺, —C(R⁺)═C(R⁺)₂, —C≡C—R⁺, —OR⁺, —SR^(∘), —S(O)R^(∘), —SO₂R^(∘),—SO₃R⁺, —SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R⁺, —NR⁺C(S)R⁺, —NR⁺C(O)N(R⁺)₂,—NR⁺C(S)N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)₂, —N(R⁺)C(═NR⁺)—R^(∘), —NR⁺CO₂R⁺,—NR⁺SO₂R^(∘), —NR⁺SO₂N(R⁺)₂, —O—C(O)R⁺, —O—CO₂R⁺, —OC(O)N(R⁺)₂, —C(O)R⁺,—C(S)R^(∘), —CO₂R⁺, —C(O)—C(O)R⁺, —C(O)N(R⁺)₂, —C(S)N(R⁺)₂,—C(O)N(R⁺)—OR⁺, —C(O)N(R⁺)C(═NR⁺)—N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)—C(O)R⁺,—C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—OR⁺, —N(R⁺)—N(R⁺)₂, —C(═NR⁺)—N(R⁺)—OR⁺,—C(R^(∘))═N—OR⁺, —P(O)(R⁺)₂, —P(O)(OR⁺)₂, —O—P(O)—OR⁺, and—P(O)(NR⁺)—N(R⁺)₂, wherein R⁺, independently, is hydrogen or analiphatic, aryl, heteroaryl, cycloaliphatic, or heterocyclyl group, ortwo independent occurrences of R⁺ that are bound to the same atom aretaken together with their intervening atom(s) to form an optionallysubstituted 5-7-membered aryl, heteroaryl, cycloaliphatic, orheterocyclyl ring. When R+ is not hydrogen, R+ may be unsubstituted orsubstituted with 1, 2, 3, or 4 substituent groups. Each R^(∘) is analiphatic, aryl, heteroaryl, cycloaliphatic, or heterocyclyl group,wherein R^(∘) is unsubstituted or substituted with 1, 2, 3, or 4substituent groups.

An alkenyl, a carbocyclic ring, or a heterocyclic ring may contain oneor more substituents and thus may be “optionally substituted”. Unlessotherwise defined above and herein, suitable substituents on anysaturated carbon of an alkenyl, a carbocyclic ring, or a heterocyclicring are selected from those listed above for the carbon atoms of anaryl or heteroaryl group and additionally include the following: ═O, ═S,═C(R*)₂, ═N—N(R*)₂, ═N—OR*, ═N—NHC(O)R*, ═N—NHCO₂R^(∘)═N—NHSO₂R^(∘) or═N—R* where R^(∘) is defined above, and each R* is independentlyselected from hydrogen or an C₁₋₆ aliphatic group that is unsubstitutedor substituted with 1, 2, 3, or 4 substituent groups.

In addition to the substituents defined above and herein, optionalsubstituents on the nitrogen of a non-aromatic heterocyclic ring alsoinclude and are generally selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —C(O)OR⁺,—C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —S(O)₂R⁺, —S(O)₂N(R⁺)₂, —C(S)N(R⁺)₂,—C(═NH)—N(R⁺)₂, or —N(R⁺)S(O)₂R⁺; wherein each R⁺ is defined above. Aring nitrogen atom of a heteroaryl or non-aromatic heterocyclic ringalso may be oxidized to form the corresponding N-hydroxy or N-oxidecompound. A nonlimiting example of such a heteroaryl having an oxidizedring nitrogen atom is N-oxidopyridyl.

As detailed above, in some embodiments, two independent occurrences ofR⁺ (or any other variable similarly defined in the specification andclaims herein) that are bound to the same atom, can be taken togetherwith their intervening atom(s) to form a monocyclic or bicyclic ringselected from 3-13-membered cycloaliphatic, 3-12-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention.

With respect to the compounds defined by generic Formula I or II, unlessotherwise specified, one or more hydrogens can be replaced by deuterium.Isotopic enrichments include e.g., at least 10%, 25%, 50%, 75%, 80%,85%, 90%, 95%, 87%, 98%, 99.0%, 99.5% and 99.8%. In one embodiment, allhydrogen atoms represented in Formula I and II are present in naturalabundance. With respect to specific compounds disclosed herein, such asthose in Table 1 and in the Exemplification section, all hydrogen atomsare present in natural abundance unless otherwise specified.

It is to be understood that, when a disclosed compound has at least onechiral center, the present invention encompasses one enantiomer freefrom the corresponding optical isomer, racemic mixture of the compoundand mixtures enriched in one enantiomer relative to its correspondingoptical isomer. When a mixture is enriched in one enantiomer relative toits optical isomers, the mixture contains, for example, an enantiomericexcess of at least 50%, 75%, 90%, 95% 99% or 99.5%.

The enantiomers of the present invention may be resolved by methodsknown to those skilled in the art, for example by formation ofdiastereoisomeric salts which may be separated, for example, bycrystallization; formation of diastereoisomeric derivatives or complexeswhich may be separated, for example, by crystallization, gas-liquid orliquid chromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic esterification; orgas-liquid or liquid chromatography in a chiral environment, for exampleon a chiral support for example silica with a bound chiral ligand or inthe presence of a chiral solvent. Where the desired enantiomer isconverted into another chemical entity by one of the separationprocedures described above, a further step is required to liberate thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

When a disclosed compound has at least two chiral centers, the presentinvention encompasses a diastereomer free of other diastereomers, a pairof diastereomers free from other diastereomeric pairs, mixtures ofdiastereomers, mixtures of diastereomeric pairs, mixtures ofdiastereomers in which one diastereomer is enriched relative to theother diastereomer(s) and mixtures of diastereomeric pairs in which onediastereomeric pair is enriched relative to the other diastereomericpair(s). When a mixture is enriched in one diastereomer ordiastereomeric pair(s) relative to the other diastereomers ordiastereomeric pair(s), the mixture is enriched with the depicted orreferenced diastereomer or diastereomeric pair(s) relative to otherdiastereomers or diastereomeric pair(s) for the compound, for example,by a molar excess of at least 50%, 75%, 90%, 95%, 99% or 99.5%.

The diastereoisomeric pairs may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. Specific procedures for chromatographically separatingdiastereomeric pairs of precursors used in the preparation of compoundsdisclosed herein are provided the examples herein.

3. Description of Exemplary Compounds

As described generally above, in some embodiments the present inventionprovides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is selected from

R¹ is an optionally substituted monocyclic or bicyclic heterocyclyl;

R² is selected from C₂-C₆ alkenyl, heteroaryl, partially unsaturatedheterocyclyl, partially unsaturated carbocyclyl, and para-substitutedphenyl, and when ring A comprises two nitrogen atoms, R² is additionallyselected from unsubstituted phenyl,

wherein R² is optionally further substituted, and wherein any twosubstituents on adjacent ring atoms in R² are optionally taken togetherwith the adjacent ring atoms to form a ring that is an aryl, acarbocyclyl, a heteroaryl, or a heterocyclyl ring;

R³, when present, is selected from chloro, fluoro, —CF₃ and —CHF₂;

n is 0 or 1;

“1” represents a point of attachment between ring A to —NH—C(O)—R¹;

“2” represents a point of attachment between ring A and R²;

“3” represents a point of attachment between ring A and —NH₂.

In some embodiments, the compound is other than:

In some embodiments, ring A is heteroaromatic. For example, ring A isselected from:

In other embodiments, n is 0.

In still other embodiments, n is 1.

In other embodiments, ring A is selected from:

In further embodiments, ring A is selected from

In some embodiments, ring A is selected from:

In some embodiments, ring A is selected from any of the ring A moietiesin the compounds set forth in Table 1.

In some embodiments, R¹ is unsubstituted.

In other embodiments, R¹ is substituted (e.g., R¹ comprises 1, 2, 3, or4 additional substituents as described herein).

In some embodiments, R¹ is selected from5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl, pyrrolidin-1-yl,1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl,6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-2H-pyran-4-yl,hexahydrocyclopenta[c]pyrrol-2(1H)-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl,isoindolin-2-yl, 4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl,2-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, and2-oxa-6-azaspiro[3.4]octan-6-yl, wherein R¹ is optionally substitutedwith up to 3 independently selected substituents.

In further embodiments, R¹ is selected from5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl, pyrrolidin-1-yl,1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl,6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-2H-pyran-4-yl,hexahydrocyclopenta[c]pyrrol-2(1H)-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl,isoindolin-2-yl, 4,6-difluoroisoindolin-2-yl,4,7-difluoroisoindolin-2-yl, 4-fluoroisoindolin-2-yl,5-fluoroisoindolin-2-yl, 4-chlorolisoindolin-2-yl,4-methoxyisoindolin-2-yl, 5-methoxyisoindolin-2-yl,5-chloroisoindolin-2-yl, 4-trifluoromethylisoindolin-2-yl,5,6-difluoroisoindolin-2-yl, 5-trifluoromethylisoindolin-2-yl,5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl,3-fluoro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl,5-(cyclopropylmethyl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl,4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl,2-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl,2-oxa-6-azaspiro[3.4]octan-6-yl, and3-((4-methylpiperazin-1-yl)methyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-6-yl.

In some embodiments, R² is unsubstituted.

In other embodiments, R² is substituted (e.g., R² comprises 1, 2, 3, or4 additional substituents as described herein).

In still other embodiments, R² is selected from —C₂-C₄ alkenyl, phenyl,4-substituted phenyl, pyridin-4-yl, isoxazol-5-yl, oxazol-5-yl,isothiazol-5-yl, thiazol-5-yl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, furan-3-yl, furan-2-yl,cyclopent-1-ene-1-yl, and 2,5-dihydrofuran-3-yl.

In certain embodiments, R² is selected from —C(CH₃)═CH₂, phenyl,4-fluorophenyl, 4-difluoromethoxyphenyl, 4-methylphenyl,3,4-difluorophenyl, pyridin-4-yl, isoxazol-5-yl, oxazol-5-yl,isothiazol-5-yl, thiazol-5-yl, 1-methyl-1H-pyrazol-4-yl,1-(2-methylpropyl)-1H-pyrazol-4-yl, 1-trifluoromethyl-1H-pyrazol-4-yl,1,5-dimethyl-1H-pyrazol-4-yl, 1-cyclobutyl-1H-pyrazol-4-yl,1-cyclopentyl-1H-pyrazol-4-yl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, furan-3-yl, furan-2-yl,5-methylfuran-2-yl, 5-methylfuran-3-yl, cyclopent-1-ene-1-yl, and2,5-dihydrofuran-3-yl.

As described generally above, in some embodiments the present inventionalso provides a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein

ring A′B′ is a fused bicyclic ring system containing at least twonitrogen atoms, wherein ring A′ is a 6-membered heterocyclyl and ring B′is a 5-membered heteroaryl;

X¹ is carbon or nitrogen;

R^(3′) and R⁴ are each independently halo, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, or halo(C₁-C₄)alkoxy;

R⁵ is halo, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,monocyclic heterocyclyl, or (C₁-C₄)alkyl optionally substituted withmonocyclic heterocyclyl, wherein each of said heterocyclyl areoptionally and independently substituted with 1 to 2 groups selectedfrom halo, (C₁-C₄)alkyl, and halo(C₁-C₄)alkyl;

n′ is 0 or 1; and

p and t are each independently 0, 1, or 2.

In certain embodiments, the compound of Formula II is of the Formula:

or a pharmaceutically acceptable salt thereof.

In other embodiments, the compound of Formula II is of the Formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments of Formula II and those described in precedingparagraphs 53 and 54, ring A′B′ is selected from

wherein the remaining values are as described above for Formula II.Alternatively ring A′B′ is selected from

wherein the remaining values are as described above for Formula II.

In certain embodiments of Formula II and those described in precedingparagraphs 53 and 54, p is 0 or 1, wherein the remaining values are asdescribed above for Formula II and the embodiment of paragraph 55.

In certain embodiments of Formula II and those described in precedingparagraphs 53 and 54, R⁴, if present, is halo, wherein the remainingvalues are as described above for Formula II and the embodiment ofparagraph 55 or 56.

In certain embodiments of Formula II and those described in precedingparagraphs 53 and 54, t is 0 or 1, wherein the remaining values are asdescribed above for Formula II and the embodiment of paragraph 55, 56,or 57.

In certain embodiments of Formula II and those described in precedingparagraphs 53 and 54, R⁵, if present, is selected from halo(C₁-C₄)alkyland (C₁-C₄)alkyl, wherein the remaining values are as described abovefor Formula II and the embodiment of paragraph 55, 56, 57, or 58.

In certain embodiments of Formula II and those described in precedingparagraphs 53 and 54, ring A′B′ and (R⁵)_(t) taken together are selectedfrom

wherein the remaining values are as described above for Formula II andthe embodiment of paragraph 55, 56, 57, 58, or 59.

Although, as indicated above, various embodiments and aspects thereoffor a variable in any of the formulas described herein (e.g., a compoundof Formula I, II or any of compounds 100-128 or any of those in Tables 2or 3) may be selected from a group of chemical moieties, the inventionalso encompasses as further embodiments and aspects thereof situationswhere such variable is: a) selected from any subset of chemical moietiesin such a group; and b) any single member of such a group. Further,where various embodiments and aspects thereof are set forth individuallyfor each variable in any of the formulas described herein (e.g., acompound of Formula I, II or any of compounds 100-128 or any of those inTables 2 or 3), the invention encompasses all possible combinations ofthe different embodiments and aspects for each of the variables in theFormula.

Exemplary compounds of and useful in the present invention are set forthin Table 1 below. In certain embodiments, the present invention providesa compound depicted in Table 1, or a pharmaceutically acceptable saltthereof.

TABLE 1 Exemplary Compounds MS MS No. Structure Calc. found ¹H NMR (Data(400 MHz, DMSO-d₆) 100

366 367 δ 8.61 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.78 (s, 1H),7.48-7.43 (m, 3H), 7.24 (t, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 1H),6.58 (d, J = 12.8 Hz, 1H), 5.39 (br, 2H), 4.80 (d, J = 6.4 Hz, 4H). 101

320 321 δ 8.61 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.68 (s, 1H), 7.62 (d,J = 7.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.43 (d, J = 5.2 Hz, 1H),7.39 (s, 1H), 7.33 (t, J = 7.6 Hz, 1H), 5.09 (s, 2H), 4.77 (d, J = 6.4Hz, 4H). 102

338 339 δ 8.61 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.68 (s, 1H),7.65-7.62 (m, 2H), 7.43 (d, J = 5.2 Hz, 1H), 7.38 (s, 1H), 7.34 (t, J =8.8 Hz, 2H), 5.01 (br, 2H), 4.76 (d, J = 6.0 Hz, 4H). 103

321 322 δ 8.62-8.61 (m, 3H), 8.50 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 4.8Hz, 2H), 7.74 (s, 1H), 7.53 (s, 1H), 7.44 (d, J = 4.0 Hz, 1H), 5.39 (br,2H), 4.78 (d, J = 6.0 Hz, 4H) 104

340 341 δ 8.07 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.60-7.56(m, 2H), 7.51 (s, 1H), 7.24 (t, J = 8.8 Hz, 2H), 5.84 (br, 2H),3.64-3.59 (m, 2H), 3.18 (dd, J = 10.8 Hz, 4.0 Hz, 2H), 2.67-2.64 (m,2H), 1.83-1.69 (m, 3H), 1.62-1.52 (m, 1H), 1.48- 1.43 (m, 2H). 105

300 301 δ 8.07 (s, 1H), 7.91-7.87 (m, 3H), 7.60 (s, 1H), 7.23 (t, J =8.8 Hz, 2H), 5.18 (br, 2H), 3.42 (t, J = 6.8 Hz, 4H), 1.88 (t, J = 6.4Hz, 4H). 106

315 316 δ 9.30 (br, 1H), 8.12 (s, 1H), 8.09 (s, 1H), 7.90-7.86 (m, 2H),7.24 (t, J = 8.8 Hz, 2H), 5.29 (br, 2H), 3.94- 3.90 (m, 2H), 3.40-3.36(m, 2H), 2.73-2.70 (m, 1H), 1.77-1.66 (m, 4H). 107

300 301 δ 8.21 (br, 1H), 799-7.95 (m, 2H), 7.54 (d, J = 8.4 Hz, 1H),7.21 (t, J = 8.8 Hz, 2H), 7.17 (d, J = 8.0 Hz, 1H), 5.11 (br, 2H),3.39-3.38 (m, 4H), 1.86 (s, 4H). 108

283 284 CD₃OD δ 8.57 (d, J = 6.4 Hz, 2H), 8.20 (s, 1H), 7.99 (s, 1H),7.90 (d, J = 6.4 Hz, 2H), 3.55 (t, J = 6.4 Hz, 4H), 2.02 (s, 4H). 109

315 316 δ 10.03 (br, 1H), 7.98-7.94 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H),7.24 (t, J = 8.8 Hz, 3H), 5.07 (br, 2H), 3.91 (dd, J = 11.6 Hz, 2.0 Hz,2H), 3.38-3.32 (m, 2H), 2.80-2.74 (m, 1H), 1.78- 1.64 (m, 4H). 110

301 302 δ 8.71 (br, 1H), 8.27-8.2 (m, 2H), 8.20 (s, 1H), 7.26 (t, J =8.8 Hz, 2H), 5.23 (br, 2H), 3.43 (s, 4H), 1.87 (s, 4H) 111

283 284 δ 8.56 (m, 2H), 8.30 (m, 1H), 7.90 (m, 2H), 7.25 (d, J = 3.6 Hz,1H), 7.17 (d, J = 4.0 Hz, 1H), 5.40 (s, 2H), 3.40-3.37 (m, 4H), 1.86 (m,4H). 112

317 318 δ 7.46-7.43 (m, 2H), 7.35 (br, 1H), 7.22 (t, J = 8.8 Hz, 2H),7.06 (t, J = 8.4 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 5.25 (br, 2H),3.35-3.34 (m, 4H), 1.85 (s, 4H). 113

367 368 δ 8.54 (s, 2H), 7.81 (s, 1H), 7.48- 7.45 (m, 2H), 7.24 (t, J =8.8 Hz, 2H), 7.11 (t, J = 8.4 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 5.43(br, 2H), 4.81 (s, 4H). 114

317 318 δ 7.45 (t, J = 6.4 Hz, 3H), 7.23 (t, J = 9.0 Hz, 2H), 7.14 (d, J= 8.8 Hz, 1H), 6.57 (d, J = 13.2 Hz, 1H), 5.26 (s, 2H), 3.36 (t, J = 6.6Hz, 4H), 1.85 (t, J = 6.4 Hz, 4H). 115

332 333 δ 9.07 (s, 1H), 7.45 (t, J = 6.6 Hz, 2H), 7.30 (d, J = 8.4 Hz,1H), 7.24 (t, J = 8.8 Hz, 2H), 6.59 (d, J = 13.2 Hz, 1H), 5.30 (s, 2H),3.90 (d, J = 10.8 Hz, 2H), 3.38-3.35 (m, 2H), 2.66-2.59 (m, 1H),1.75-1.61 (m, 4H). 116

335 336 δ 7.50-7.43 (m, 3H), 7.27 (bs, 1H), 7.18 (d, J = 8.8 Hz, 1H),6.57 (d, J = 13.6 Hz, 1H), 5.35 (s, 2H), 3.36 (t, J = 6.4 Hz, 4H), 1.85(t, J = 6.4 Hz, 4H). 117

335 336 δ 7.49-7.42 (m, 2H), 7.35 (br, 1H), 7.28-7.26 (m, 1H), 7.11 (t,J = 8.4 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 5.35 (br, 2H), 3.37 (s, 4H),1.85 (s, 4H). 118

332 333 δ 9.02 (br, 1H), 7.46-7.43 (m, 2H), 7.23 (t, J = 8.4 Hz, 2H),7.10 (t, J = 8.4 Hz, 1H), 6.61 (t, J = 8.4 Hz, 1H), 5.23 (br, 2H),3.91-3.88 (m, 2H), 3.38-3.35 (m, 2H), 2.68-2.62 (m, 1H), 1.78-1.61 (m,4H). 119

367 368 CD₃OD δ 8.41 (s, 2H), 7.41-3.67 (m, 2H), 7.08 (d, J = 8.4 Hz,1H), 704-6.98 (m, 2H), 6.52 (d, J = 12.4 Hz, 1H), 4.79 (s, 4H). 120

350 351 δ 8.66 (s, 1H), 8.55 (s, 2H), 8.00- 7.96 (m, 2H), 7.58 (d, J =8.4 Hz, 1H), 7.23 (t, J = 8.8 Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 5.21(s, 2H), 4.85 (br, 4H). 121

351 352 δ 9.14 (br, 1H), 8.56 (s, 2H), 8.29- 8.25 (m, 3H), 7.27 (t, J =8.8 Hz, 2H), 5.31 (br, 2H), 4.88 (br, 4H). 122

320 321 CD₃OD δ 8.47 (s, 1H), 8.39 (d, J = 5.2 Hz, 1H), 7.65 (s, 1H),7.53 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 5.2 Hz, 1H), 7.32 (t, J = 8.0 Hz,2H), 7.11 (t, J = 7.4 Hz, 1H), 4.82 (s, 4H).

TABLE 2 Exemplary Compounds MS MS No. Structure Calc. found ¹H NMR Data(400 MHz, DMSO-d₆) 123

452 453 δ 8.49 (s, 1H), 7.73-7.58 (m, 3H), 7.52 (s, 1H), 7.26 (dd, J =15.5, 6.7 Hz, 3H), 4.03 (s, 2H), 3.77 (s, 3H), 3.48-3.34 (m, 4H),3.30-3.19 (m, 1H), 3.12 (d, J = 10.1 Hz, 1H), 2.45- 2.36 (m, 1H), 2.15(d, J = 75.5 Hz, 3H), 1.81 (s, 1H), 1.53 (dd, J = 54.6, 29.6 Hz, 4H),1.32 (s, 1H). 124

478 479 δ 8.51 (s, 1H), 7.66 (s, 1H), 7.65-7.60 (m, 2H), 7.24 (dd, J =17.5, 8.6 Hz, 3H), 6.89 (d, J = 7.3 Hz, 2H), 6.83- 6.73 (m, 1H), 4.02(s, 2H), 3.73 (s, 3H), 3.46 (m, 4H), 3.28 (d, J = 9.6 Hz, 1H), 3.16 (d,J = 10.3 Hz, 1H), 2.45- 2.35 (m, 1H), 2.19 (d, J = 54.6 Hz, 3H), 1.86(s, 1H), 1.55 (m, 4H), 1.36 (s, 1H). 125

448 449 δ 8.97 (s, 1H), 7.68 (s, 1H), 7.67- 7.59 (m, 2H), 7.31-7.25 (m,4H), 7.23-7.17 (m, 3H), 3.94 (s, 2H), 3.76-2.6 (m, 2H), 3.51-3.46 (m,6H), 2.39-2.31 (m, 2H), 1.84- 1.40 (m, 1H), 1.25-1.01 (m, 1H). 126

299 300 δ 10.64 (s, 1H), 7.92-7.74 (m, 2H), 7.67 (dd, J = 8.6, 1.0 Hz,2H), 7.52-7.36 (m, 2H), 7.20 (t, J = 7.4 Hz, 1H), 4.08 (s, 2H), 2.56 (d,J = 0.9 Hz, 3H). 128

436 437 δ 8.54 (s, 1H), 8.50 (s, 1H), 7.98 (dd, J = 8.9, 5.6 Hz, 2H),7.57 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17(d, J = 8.2 Hz, 1H), 5.31-5.10 (m, 3H), 4.81 (s, 4H), 3.77 (s, 2H),3.68-3.57 (m, 2H), 3.29-3.24 (m, 1H), 3.24- 3.17 (m, 1H). 129

327 328 δ 8.80 (s, 1H), 7.69 (s, 1H), 7.61 (d, J = 7.7 Hz, 2H), 7.40 (t,J = 8.0 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), 4.05 (s, 2H), 3.70 (s, 4H),3.61-3.46 (m, 4H), 1.80-1.63 (m, 4H). 130

341 342 δ 8.88 (s, 1H), 7.69 (s, 1H), 7.61 (d, J = 7.7 Hz, 2H), 7.40 (t,J = 8.0 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), 3.94 (s, 2H), 3.76 (t, J =7.1 Hz, 2H), 3.58-3.49 (m, 2H), 3.47 (s, 2H), 3.43-3.34 (m, 2H), 1.74(t, J = 7.1 Hz, 2H), 1.49 (t, J = 5.5 Hz, 4H). 131

355 356 δ 8.86 (s, 1H), 7.71 (s, 1H), 7.70- 7.62 (m, 2H), 7.43-7.34 (m,1H), 7.32-7.19 (m, 3H), 7.15 (t, J = 8.9 Hz, 1H), 4.81 (s, 4H), 4.05 (s,2H). 132

356 357 CD₃OD δ 8.41 (s, 1H), 7.73 (s, 1H), 7.71- 7.61 (m, 3H),7.24-7.14 (m, 2H), 4.90 (s, 2H), 4.84 (s, 2H). 133

355 356 δ 8.82 (s, 1H), 7.71 (s, 1H), 7.69- 7.62 (m, 2H), 7.39 (dd, J =8.3, 5.1 Hz, 1H), 7.25 (dd, J = 18.3, 9.4 Hz, 3H), 7.15 (t, J = 8.9 Hz,1H), 4.74 (d, J = 12.1 Hz, 4H), 4.05 (s, 2H). 134

338 339 δ 8.89 (s, 1H), 8.48 (d, J = 3.7 Hz, 1H), 7.81 (d, J = 8.2 Hz,1H), 7.71 (s, 1H), 7.70-7.61 (m, 2H), 7.33 (dd, J = 7.7, 4.9 Hz, 1H),7.27 (t, J = 8.8 Hz, 2H), 4.77 (d, J = 9.6 Hz, 4H), 4.06 (s, 2H). 135

317 318 δ 8.86 (s, 1H), 7.67 (s, 1H), 7.63 (dd, J = 8.9, 4.7 Hz, 2H),7.26 (t, J = 8.8 Hz, 2H), 4.66 (d, J = 14.3 Hz, 4H), 4.09 (d, J = 19.7Hz, 4H), 4.02 (d, J = 11.6 Hz, 2H). 136

304 305 CD₃OD δ 7.72 (s, 1H), 7.69-7.58 (m, 2H), 7.29-7.07 (m, 2H), 4.03(dd, J = 10.2, 2.8 Hz, 2H), 3.52 (td, J = 11.4, 3.1 Hz, 2H), 2.83-2.65(m, 1H), 1.96-1.75 (m, 4H). 137

345 346 δ 8.88 (s, 1H), 7.67 (s, 1H), 7.66- 7.58 (m, 2H), 7.25 (t, J =8.8 Hz, 2H), 4.33 (s, 4H), 3.92 (s, 2H), 3.45- 3.35 (m, 4H), 1.81-1.70(m, 4H). 139

339 340 δ 8.98 (s, 1H), 8.55 (s, 2H), 7.73 (s, 1H), 7.71-7.61 (m, 2H),7.28 (t, J = 8.8 Hz, 2H), 4.78 (s, 4H), 4.06 (s, 2H). 140

423 424 CD₃OD δ 7.80 (dd, J = 8.7, 5.5 Hz, 2H), 7.39 (d, J = 8.2 Hz,1H), 7.18 (d, J = 8.2 Hz, 1H), 7.03 (t, J = 8.8 Hz, 2H), 3.65 (dd, J =10.7, 8.1 Hz, 1H), 3.56 (dd, J = 10.6, 7.7 Hz, 1H), 3.39- 3.31 (m, 1H),3.28-3.23 (m, 1H), 2.86-2.59 (m, 8H), 2.37-2.32 (m, 0.5H), 2.26-2.08 (m,1.5H), 1.86- 1.71 (m, 5H), 1.58-1.46 (m, 1H), 1.17-1.09 (m, 1H). 141

337 338 δ 8.56 (s, 1H), 7.75-7.60 (m, 3H), 7.39-7.02 (m, 3H), 4.05 (s,2H), 3.36 (s, 4H), 1.85 (s, 4H). 142

289 290 δ 8.54 (s, 1H), 7.74-7.54 (m, 3H), 7.25 (t, J = 8.8 Hz, 2H),4.03 (s, 2H), 3.40-3.34 (m, 4H), 1.85 (s, 4H). 143

395 396 CDCl₃ δ 7.82 (s, 2H), 7.32 (s, 1H), 7.10 (t, J = 8.7 Hz, 3H),6.81 (s, 1H), 4.57 (s, 2H), 3.74-3.70 (m, 2H), 3.54- 3.44 (m, 2H), 3.38(s, 4H), 2.97 (s, 1H), 2.74 (s, 2H), 2.19-2.11 (m, 2H), 2.08-2.00 (m,2H), 1.50- 1.38 (m, 2H). 144

420 421 δ 8.53 (s, 1H), 8.38 (s, 1H), 7.72 (s, 1H), 7.52 (d, J = 8.2 Hz,1H), 7.48 (dd, J = 3.6, 1.1 Hz, 1H), 7.41 (dd, J = 5.0, 1.0 Hz, 1H),7.12 (d, J = 8.2 Hz, 1H), 7.06 (dd, J = 5.0, 3.6 Hz, 1H), 5.18 (s, 2H),4.77 (s, 4H), 3.62 (s, 2H), 2.44 (s, 4H), 1.70 (d, J = 3.3 Hz, 4H). 145

394 395 δ 8.54 (s, 1H), 8.37 (s, 1H), 7.71 (s, 1H), 7.52 (d, J = 8.2 Hz,1H), 7.48 (dd, J = 3.6, 1.0 Hz, 1H), 7.41 (dd, J = 5.0, 1.0 Hz, 1H),7.12 (d, J = 8.2 Hz, 1H), 7.06 (dd, J = 5.0, 3.7 Hz, 1H), 5.18 (s, 2H),4.77 (s, 4H), 3.44 (s, 2H), 2.16 (s, 6H). 146

419 420 δ 8.58 (s, 1H), 7.98 (dd, J = 8.8, 5.6 Hz, 2H), 7.54 (d, J = 8.2Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.22 (t, J= 8.9 Hz, 2H), 7.16 (d, J = 8.2 Hz, 1H), 5.19 (s, 2H), 4.37 (t, J = 8.4Hz, 2H), 3.97-3.89 (m, 2H), 3.85-3.80 (m, 1H), 3.43 (s, 2H), 2.18 (s,6H). 147

404 405 δ 8.49 (s, 1H), 8.07 (s, 1H), 7.98 (dd, J = 8.8, 5.7 Hz, 2H),7.57 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17 (d, J = 8.2 Hz,1H), 6.36 (s, 1H), 5.17 (s, 2H), 4.68 (s, 4H), 3.92 (t, J = 7.3 Hz, 4H),2.36-2.25 (m, 2H). 148

444 445 δ 8.55 (d, J = 8.5 Hz, 2H), 8.03- 7.92 (m, 2H), 7.57 (d, J = 7.9Hz, 2H), 7.22 (t, J = 8.7 Hz, 2H), 7.17 (d, J = 8.2 Hz, 1H), 6.70 (s,1H), 5.19 (s, 2H), 4.81 (s, 4H), 3.06 (s, 2H), 2.58 (s, 4H), 2.29 (s,3H). 149

446 447 CD₃OD δ 8.43 (s, 1H), 7.81 (s, 2H), 7.42 (s, 1H), 7.30 (s, 1H),7.21 (s, 1H), 7.03 (t, J = 8.7 Hz, 2H), 4.81 (s, 4H), 3.41-3.27 (m, 2H),2.90 (s, 1H), 2.78 (s, 2H), 2.64 (s, 3H), 1.98 (m, 4H). 150

434 435 δ 8.50 (s, 1H), 8.15 (s, 1H), 7.98 (dd, J = 8.8, 5.6 Hz, 2H),7.57 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17 (d, J = 8.2 Hz,1H), 6.86 (s, 1H), 5.18 (s, 2H), 4.70 (s, 4H), 3.71 (t, J = 4.0 Hz, 4H),3.43 (t, J = 4.0 Hz, 4H). 151

363 364 δ 8.54 (s, 1H), 8.46 (s, 1H), 7.98 (dd, J = 8.8, 5.7 Hz, 2H),7.57 (d, J = 8.2 Hz, 1H), 7.29 (s, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17(d, J = 8.2 Hz, 1H), 5.18 (s, 2H), 4.78 (s, 4H), 3.33- 3.32 (s, 3H). 152

410 411 CDCl₃ δ 7.83 (s, 2H), 7.36 (d, J = 7.4 Hz, 1H), 7.11 (dd, J =17.7, 9.0 Hz, 3H), 6.77 (s, 1H), 4.59 (s, 2H), 3.77 (s, 2H), 3.58 (s,2H), 3.44 (d, J = 9.9 Hz, 2H), 3.20-3.12 (m, 1H), 3.06 (s, 2H), 2.96 (s,2H), 2.63 (s, 2H), 2.46 (d, J = 8.6 Hz, 2H), 2.42 (s, 3H). 153

383 384 δ 10.32 (s, 1H), 7.96 (dd, J = 8.8, 5.6 Hz, 2H), 7.66 (d, J =8.3 Hz, 1H), 7.22 (t, J = 8.5 Hz, 3H), 5.31 (s, 2H), 3.62 (s, 2H), 2.97(t, J = 5.3 Hz, 2H), 2.81-2.63 (m, 2H), 2.43 (s, 3H). 154

406 407 δ 8.56 (s, 1H), 8.38 (s, 1H), 7.98 (dd, J = 8.8, 5.6 Hz, 2H),7.72 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17(d, J = 8.2 Hz, 1H), 5.18 (s, 2H), 4.78 (s, 4H), 3.45 (s, 2H), 2.17 (s,6H). 155

432 433 δ 8.56 (s, 1H), 8.40 (s, 1H), 8.03- 7.94 (m, 2H), 7.73 (s, 1H),7.57 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17 (d, J = 8.2 Hz,1H), 5.18 (s, 2H), 4.78 (s, 4H), 3.64 (s, 2H), 2.47 (s, 4H), 1.71 (s,4H). 156

338 339 δ 8.65 (s, 1H), 8.55 (s, 2H), 7.53 (d, J = 8.2 Hz, 1H), 7.49(dd, J = 3.6, 1.0 Hz, 1H), 7.41 (dd, J = 5.0, 1.0 Hz, 1H), 7.12 (d, J =8.2 Hz, 1H), 7.06 (dd, J = 5.0, 3.7 Hz, 1H), 5.20 (s, 2H), 4.84 (s, 4H).157

404 405 δ 8.50 (s, 1H), 8.02-7.93 (m, 2H), 7.69 (d, J = 2.5 Hz, 1H),7.57 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17 (d, J = 8.2 Hz,1H), 6.84 (d, J = 2.3 Hz, 1H), 5.17 (s, 2H), 4.68 (d, J = 21.5 Hz, 4H),3.87 (t, J = 7.2 Hz, 4H), 2.37-2.33 (m, 2H). 158

434 435 δ 8.53 (s, 1H), 8.21 (d, J = 2.3 Hz, 1H), 7.98 (dd, J = 8.8, 5.6Hz, 2H), 7.57 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 7.23 (t, J = 8.9 Hz,2H), 7.17 (d, J = 8.2 Hz, 1H), 5.18 (s, 2H), 4.71 (d, J = 20.8 Hz, 4H),3.76 (t, J = 4.0 Hz, 4H), 3.17 (t, J = 4.0 Hz, 4H). 159

447 448 δ 8.52 (s, 1H), 8.20 (d, J = 2.4 Hz, 1H), 7.98 (dd, J = 8.9, 5.6Hz, 2H), 7.57 (d, J = 8.2 Hz, 1H), 7.37 (s, 1H), 7.22 (t, J = 8.9 Hz,2H), 7.17 (d, J = 8.2 Hz, 1H), 5.17 (s, 2H), 4.70 (d, J = 21.9 Hz, 4H),3.20 (s, 4H), 2.51 (s, 4H), 2.26 (s, 3H). 160

447 448 δ 8.50 (s, 1H), 8.12 (s, 1H), 7.98 (dd, J = 8.8, 5.6 Hz, 2H),7.57 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17 (d, J = 8.2 Hz,1H), 6.85 (s, 1H), 5.18 (s, 2H), 4.65 (d, J = 30.1 Hz, 4H), 3.48 (s,4H), 2.42 (s, 4H), 2.23 (s, 3H). 161

389 390 δ 9.15 (d, J = 1.8 Hz, 1H), 8.60 (s, 1H), 8.48 (dd, J = 4.7, 1.5Hz, 1H), 8.37 (s, 1H), 8.28 (d, J = 8.1 Hz, 1H), 7.72 (s, 1H), 7.68 (d,J = 8.2 Hz, 1H), 7.42 (dd, J = 7.9, 4.6 Hz, 1H), 7.19 (d, J = 8.2 Hz,1H), 5.31 (s, 2H), 4.79 (s, 4H), 3.44 (s, 2H), 2.16 (s, 6H). 162

406 407 δ 8.56 (s, 1H), 8.52 (s, 1H), 7.98 (dd, J = 8.8, 5.6 Hz, 2H),7.57 (d, J = 8.2 Hz, 1H), 7.46 (s, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17(d, J = 8.2 Hz, 1H), 5.18 (s, 2H), 4.82 (s, 4H), 3.65 (s, 2H), 2.27 (s,6H). 163

355 356 δ 10.28 (s, 1H), 7.68 (d, J = 1.0 Hz, 1H), 7.46 (d, J = 8.3 Hz,1H), 7.20 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 2.9 Hz, 1H), 6.55 (dd, J =3.3, 1.8 Hz, 1H), 5.34 (s, 2H), 3.62 (s, 2H), 2.96 (d, J = 5.5 Hz, 2H),2.72 (t, J = 5.6 Hz, 2H), 2.43 (s, 3H). 164

398 399 δ 10.36 (s, 1H), 9.12 (d, J = 1.8 Hz, 1H), 8.49 (dd, J = 4.7,1.5 Hz, 1H), 8.26 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.42(dd, J = 8.0, 4.8 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 5.43 (s, 2H), 4.65(dt, J = 47.6 Hz, J = 4.8 Hz, 2H), 3.80 (s, 2H), 3.03- 2.94 (m, 3H),2.89 (t, J = 4.8 Hz, 3H). 165

415 416 δ 10.31 (s, 1H), 7.96 (dd, J = 8.8, 5.6 Hz, 2H), 7.67 (d, J =8.3 Hz, 1H), 7.23 (t, J = 8.8 Hz, 3H), 5.31 (s, 2H), 4.65 (dt, J = 47.6Hz, J = 4.8 Hz, 2H), 3.79 (s, 2H), 3.01- 2.93 (m, 3H), 2.89 (t, J = 4.8Hz, 3H). 166

412 413 CD₃OD δ 7.79 (dd, J = 8.7, 5.5 Hz, 2H), 7.39 (d, J = 7.9 Hz,1H), 7.18 (d, J = 8.2 Hz, 1H), 7.03 (t, J = 8.8 Hz, 2H), 3.59 (dd, J =10.8, 7.9 Hz, 2H), 3.42 (dd, J = 10.9, 2.5 Hz, 2H), 2.90 (t, J = 6.3 Hz,4H), 2.76-2.67 (m, 4H), 2.62-2.51 (m, 8H). 167

359 360 δ 8.39 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 1.0 Hz,1H), 7.49 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.51-6.44 (m,1H), 5.03 (s, 2H), 4.52 (dt, J = 47.6 Hz, J = 4.8 Hz, 2H), 3.62 (dd, J =10.7, 8.1 Hz, 2H), 3.33-3.31 (m, 2H), 2.81 (s, 2H), 2.73 (t, J = 4.9 Hz,1H), 2.67- 2.60 (m, 3H), 2.51-2.50 (m, 2H). 168

462 463 δ 8.56 (s, 1H), 8.39 (s, 1H), 7.98 (dd, J = 8.9, 5.6 Hz, 2H),7.72 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 8.9 Hz, 2H), 7.17(d, J = 8.2 Hz, 1H), 5.18 (s, 2H), 4.78 (s, 4H), 3.54 (s, 2H), 2.60 (s,4H), 2.49- 2.37 (m, 4H), 2.33 (s, 3H). 169

438 439 δ 8.29 (s, 1H), 8.01-7.92 (m, 2H), 7.52 (t, J = 7.4 Hz, 1H),7.21 (dd, J = 12.3, 5.5 Hz, 2H), 7.16 (d, J = 8.2 Hz, 1H), 5.08 (s, 2H),3.62 (dd, J = 10.6, 8.0 Hz, 2H), 3.29 (dd, J = 10.9, 2.9 Hz, 2H), 2.78(s, 2H), 2.70 (d, J = 11.5 Hz, 2H), 2.65-2.56 (m, 2H), 2.45 (d, J = 2.5Hz, 2H), 2.11 (s, 3H), 1.93-1.83 (m, 3H), 1.76 (d, J = 10.8 Hz, 2H),1.41- 1.34 (m, 2H). 170

376 377 δ 8.58 (s, 1H), 7.98 (dd, J = 8.9, 4.5 Hz, 2H), 7.54 (d, J = 8.2Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.20 (dt, J = 16.5, 8.6 Hz, 5H), 5.19(s, 2H), 4.36 (t, J = 8.4 Hz, 2H), 3.98-3.86 (m, 2H), 3.80-3.77 (m, 1H),2.30 (s, 3H). 171

352 353 δ 9.14 (d, J = 1.7 Hz, 1H), 8.48 (dd, J = 4.7, 1.6 Hz, 1H),8.31-8.24 (m, 1H), 8.22 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.42 (dd, J =7.4, 4.7 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 5.23 (s, 2H), 3.52-3..39 (m,4H), 3.13 (d, J = 10.0 Hz, 1H), 2.69 (s, 1H), 2.61 (d, J = 11.8 Hz, 2H),2.53 (s, 1H), 1.85 (s, 1H), 1.65-1.62 (m, 1H), 1.60-1.50 (m, 1H), 1.48-1.50 (m, 3H). 172

411 412 δ 8.26 (d, J = 6.8 Hz, 1H), 8.02- 7.93 (m, 2H), 7.54 (d, J = 8.2Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.16 (dd, J = 8.2, 3.9 Hz, 1H), 5.09(s, 2H), 4.61 (dd, J = 12.3, 5.7 Hz, 2H), 4.31 (t, J = 6.3 Hz, 2H), 3.88(p, J = 6.8 Hz, 1H), 3.51 (dd, J = 10.5, 7.5 Hz, 2H), 3.41-3.34 (m, 2H),3.01- 2.88 (m, 1H), 2.55 (dd, J = 8.6, 5.4 Hz, 2H), 2.04-1.98 (m, 2H),1.17- 1.10 (m, 2H). 173

361 362 δ 8.61 (s, 1H), 8.55 (s, 1H), 8.50 (d, J = 5.0 Hz, 1H), 7.88 (d,J = 8.9 Hz, 2H), 7.51 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 4.9 Hz, 1H),7.15 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.9 Hz, 2H), 5.07 (s, 2H), 4.83(s, 4H), 3.78 (s, 3H). 174

359 360 δ 8.36 (s, 1H), 7.67 (d, J = 0.8 Hz, 1H), 7.34 (d, J = 8.1 Hz,1H), 7.13 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 3.2 Hz, 1H), 6.55 (dd, J =3.3, 1.8 Hz, 1H), 5.09 (s, 2H), 4.53 (dt, J = 48.0, J = 4.9 Hz, 2H),3.59 (dd, J = 10.6, 8.0 Hz, 2H), 3.30 (d, J = 2.5 Hz, 2H), 2.80 (s, 2H),2.73 (t, J = 4.9 Hz, 1H), 2.69-2.57 (m, 3H), 2.48 (s, 2H). 175

421 422 δ 8.36 (s, 1H), 7.67 (d, J = 0.9 Hz, 1H), 7.44 (t, J = 7.5 Hz,1H), 7.37- 7.27 (m, 2H), 7.18 (t, J = 7.4 Hz, 2H), 7.13 (d, J = 8.2 Hz,1H), 6.73 (d, J = 3.2 Hz, 1H), 6.55 (dd, J = 3.3, 1.8 Hz, 1H), 5.09 (s,2H), 3.64 (s, 2H), 3.57 (dd, J = 14.0, 5.9 Hz, 2H), 3.31 (d, J = 13.8Hz, 2H), 2.80 (s, 2H), 2.65-2.57 (m, 2H), 2.43 (d, J = 6.9 Hz, 2H). 176

449 450 δ 8.30 (s, 1H), 7.97 (dd, J = 8.9, 5.6 Hz, 2H), 7.53 (d, J = 8.2Hz, 1H), 7.44 (t, J = 6.7 Hz, 1H), 7.33-7.26 (m, 1H), 7.24-7.14 (m, 5H),5.08 (s, 2H), 3.72-3.53 (m, 4H), 3.30 (s, 2H), 2.81 (s, 2H), 2.76-2.61(m, 2H), 2.46-2.44 (m, 2H). 177

421 422 δ 8.43-8.30 (m, 2H), 7.68 (d, J = 1.0 Hz, 1H), 7.51-7.38 (m,2H), 7.35-7.24 (m, 2H), 7.17 (dd, J = 15.9, 8.0 Hz, 2H), 6.50-6.43 (m,1H), 5.03 (s, 2H), 3.72-3.54 (m, 4H), 3.30 (s, 2H), 2.82 (s, 2H), 2.65-2.56 (m, 2H), 2.46 (d, J = 9.1 Hz, 2H). 178

460 461 δ 8.50 (s, 1H), 7.99 (dd, J = 8.8, 5.6 Hz, 2H), 7.57 (d, J = 8.2Hz, 1H), 7.24 (m, 6H), 5.18 (s, 2H), 4.82 (s, 4H), 3.45 (s, 2H), 2.36(m, 7H), 2.20 (s, 4H). 179

438 439 CDCl₃ δ 7.84 (dd, J = 8.4, 5.6 Hz, 2H), 7.35 (d, J = 8.2 Hz,1H), 7.14-7.00 (m, 3H), 6.73 (s, 1H), 4.59 (s, 2H), 3.76-3.64 (m, 2H),3.48 (d, J = 8.6 Hz, 2H), 2.81-2.35 (m, 10H), 2.32 (s, 3H), 2.26-2.13(m, 3H), 1.47 (d, J = 6.6 Hz, 2H). 181

425 426 CDCl₃ δ 7.84 (dd, J = 8.7, 5.5 Hz, 2H), 7.35 (d, J = 8.1 Hz,1H), 7.11 (dd, J = 17.2, 8.4 Hz, 3H), 6.75 (s, 1H), 4.59 (s, 2H),3.90-3.65 (m, 6H), 3.48 (d, J = 7.4 Hz, 2H), 2.75 (s, 2H), 2.69-2.60 (m,1H), 2.49 (s, 4H), 2.28-2.10 (m, 2H), 1.46 (dd, J = 17.9, 12.2 Hz, 2H).182

369 370 δ 8.35 (s, 1H), 7.66 (d, J = 0.9 Hz, 1H), 7.34 (d, J = 8.1 Hz,1H), 7.13 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 3.3 Hz, 1H), 6.55 (dd, J =3.3, 1.8 Hz, 1H), 5.10 (s, 2H), 4.55 (q, J = 6.6 Hz, 2H), 4.46 (t, J =5.9 Hz, 2H), 3.68-3.50 (m, 3H), 3.25 (d, J = 49.1 Hz, 2H), 2.83 (s, 2H),2.53 (d, J = 9.5 Hz, 2H), 2.44-2.36 (m, 2H). 183

387 388 δ 8.32 (d, J = 14.9 Hz, 1H), 8.01- 7.93 (m, 2H), 7.53 (d, J =8.2 Hz, 1H), 7.27-7.18 (m, 2H), 7.16 (d, J = 8.2 Hz, 1H), 5.08 (s, 2H),4.53 (dt, J = 48.0, J = 4.9 Hz, 2H), 3.61 (dd, J = 10.7, 8.1 Hz, 2H),3.34-3.31 (m, 2H), 2.81 (s, 2H), 2.73 (t, J = 5.0 Hz, 1H), 2.70-2.57 (m,3H), 2.49 (s, 2H). 184

327 328 CD₃OD δ 8.30 (d, J = 2.3 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J = 8.4Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.37 (t, J = 2.4 Hz, 1H), 3.66-3.46(m, 4H), 3.34 (s, 2H), 3.10 (s, 2H), 3.06-2.92 (m, 2H), 2.71 (s, 3H).185

339 340 δ 8.67 (s, 1H), 8.49 (s, 1H), 8.35 (s, 1H), 7.82 (d, J = 9.2 Hz,1H), 7.69 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H),6.48 (s, 1H), 5.15 (s, 2H), 4.79 (d, J = 17.4 Hz, 4H). 186

367 368 δ 8.60 (s, 1H), 8.49 (s, 1H), 7.98 (dd, J = 8.6, 5.7 Hz, 2H),7.81 (d, J = 7.1 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 8.9 Hz,2H), 7.17 (d, J = 8.2 Hz, 1H), 5.20 (s, 2H), 4.79 (d, J = 16.5 Hz, 4H).187

379 380 δ 8.58 (s, 1H), 8.49 (s, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.81 (d,J = 6.8 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H),6.96 (d, J = 8.8 Hz, 2H), 5.08 (s, 2H), 4.79 (d, J = 17.6 Hz, 4H), 3.78(s, 3H). 188

413 414 δ 8.21 (s, 1H), 8.03-7.90 (m, 2H), 7.53 (d, J = 8.2 Hz, 1H),7.20 (dt, J = 18.7, 8.9 Hz, 3H), 5.25-5.00 (m, 1H), 5.09 (s, 2H),3.66-3.45 (m, 4H), 3.34 (d, J = 3.9 Hz, 2H), 3.07- 2.94 (m, 2H), 2.79(p, J = 6.7 Hz, 1H), 2.65 (s, 2H), 1.99-1.80 (m, 2H), 1.27-1.20 (m, 2H).189

385 386 δ 8.25 (s, 1H), 7.70-7.63 (m, 1H), 7.34 (d, J = 8.1 Hz, 1H),7.13 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 3.3 Hz, 1H), 6.55 (dd, J = 3.3,1.8 Hz, 1H), 5.20-5.03 (m, 3H), 3.61-3.47 (m, 4H), 3.33 (s, 1H), 3.31(d, J = 3.7 Hz, 1H), 3.07-3.02 (m, 1H), 3.01- 2.96 (m, 1H), 2.79 (p, J =6.8 Hz, 1H), 2.64 (s, 2H), 2.01-1.76 (m, 2H), 1.26-1.20 (m, 2H). 190

385 386 δ 8.32 (d, J = 17.9 Hz, 2H), 7.68 (s, 1H), 7.48 (d, J = 8.2 Hz,1H), 7.27 (d, J = 8.4 Hz, 1H), 6.47 (s, 1H), 5.11 (m, 4H), 3.35 (s, 1H),3.28- 3.17 (m, 1H), 3.02-(d, J = 24.8 Hz, 2H), 2.87-2.73 (m, 1H), 2.65(s, 2H), 1.99-1.82 (m, 2H), 1.24 (m, 2H). 191

393 394 δ 8.26 (s, 1H), 7.94 (d, J = 7.3 Hz, 2H), 7.55 (d, J = 8.2 Hz,1H), 7.40 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.17 (d, J =8.2 Hz, 1H), 5.09 (s, 2H), 4.64-4.56 (m, 2H), 4.31 (t, J = 6.3 Hz, 2H),3.94-3.83 (m, 1H), 3.57-3.46 (m, 2H), 3.42- 3.34 (m, 2H), 3.00-2.84 (m,1H), 2.55 (s, 2H), 2.08-1.94 (m, 2H), 1.18-1.11 (m, 2H). 192

363 364 δ 10.15 (s, 1H), 8.07 (d, J = 4.0 Hz, 1H), 7.99-7.90 (m, 2H),7.62 (d, J = 8.3 Hz, 1H), 7.56-7.46 (m, 1H), 7.28-7.16 (m, 3H), 6.64(dd, J = 6.5, 5.2 Hz, 1H), 6.42 (d, J = 8.1 Hz, 1H), 5.20 (s, 2H), 4.05(t, J = 6.8 Hz, 4H), 3.85 (s, 1H). 193

335 336 δ 10.22 (s, 1H), 8.07 (d, J = 3.9 Hz, 1H), 7.68 (d, J = 1.0 Hz,1H), 7.55- 7.48 (m, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 8.3 Hz,1H), 6.75 (d, J = 3.2 Hz, 1H), 6.64 (dd, J = 6.6, 5.3 Hz, 1H), 6.56 (dd,J = 3.3, 1.8 Hz, 1H), 6.41 (d, J = 8.3 Hz, 1H), 5.21 (s, 2H), 4.10-4.03(m, 4H), 3.84 (s, 1H). 194

348 349 δ 9.85 (s, 1H), 7.92 (d, J = 7.2 Hz, 2H), 7.64 (d, J = 8.4 Hz,1H), 7.55 (s, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.34-7.17 (m, 2H), 6.67 (s,1H), 5.19 (s, 2H), 4.09 (t, J = 5.4 Hz, 2H), 3.83 (s, 2H), 3.48 (s, 2H),3.10- 2.95 (m, 2H). 195

345 346 δ 10.15 (s, 1H), 8.07 (d, J = 3.9 Hz, 1H), 7.93 (d, J = 7.3 Hz,2H), 7.64 (d, J = 8.3 Hz, 1H), 7.55-7.47 (m, 1H), 7.41 (t, J = 7.6 Hz,2H), 7.30 (t, J = 7.3 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 6.68-6.57 (m,1H), 6.42 (d, J = 8.3 Hz, 1H), 5.19 (s, 2H), 4.11- 4.04 (m, 4H), 3.86(s, 1H). 196

353 354 CD₃OD δ 7.94-7.86 (m, 2H), 7.62 (d, J = 8.3 Hz, 1H), 7.43 (t, J= 7.6 Hz, 2H), 7.39-7.31 (m, 2H), 3.70 (d, J = 18.4 Hz, 4H), 3.35 (d, J= 3.7 Hz, 2H), 2.71 (d, J = 21.9 Hz, 4H), 2.14 (s, 3H). 197

334 335 δ 8.88 (s, 1H), 7.93 (d, J = 7.7 Hz, 2H), 7.58 (d, J = 8.2 Hz,1H), 7.39 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.19-7.10 (m,2H), 6.91 (s, 1H), 5.09 (s, 2H), 4.71 (s, 2H), 4.07 (t, J = 5.0 Hz, 2H),3.92 (t, J = 5.2 Hz, 2H). 198

348 349 δ 10.12 (s, 1H), 7.68 (d, J = 1.0 Hz, 1H), 7.41 (d, J = 8.0 Hz,1H), 7.39- 6.96 (m, 6H), 6.74 (d, J = 3.2 Hz, 1H), 6.61-6.51 (m, 1H),5.17 (s, 2H), 3.53 (d, J = 10.6 Hz, 3H), 3.38 (d, J = 17.4 Hz, 2H), 3.22(s, 2H). 199

379 380 δ 8.32 (s, 1H), 7.96-7.90 (m, 2H), 7.56 (d, J = 8.2 Hz, 1H),7.40 (t, J = 7.6 Hz, 2H), 7.28 (dd, J = 9.1, 5.5 Hz, 1H), 7.17 (d, J =8.2 Hz, 1H), 5.09 (s, 2H), 4.56 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0Hz, 2H), 3.65 (dd, J = 10.7, 8.1 Hz, 2H), 3.60- 3.51 (m, 1H), 3.32 (d, J= 3.3 Hz, 2H), 2.84 (s, 2H), 2.56-2.51 (m, 2H), 2.42 (dd, J = 9.0, 2.6Hz, 2H). 201

355 356 δ 8.36 (s, 1H), 7.97 (dd, J = 8.7, 5.7 Hz, 2H), 7.53 (t, J = 8.6Hz, 1H), 7.23 (q, J = 9.1 Hz, 2H), 7.16 (d, J = 8.2 Hz, 1H), 5.11 (s,2H), 3.59 (dd, J = 10.6, 7.5 Hz, 2H), 3.40 (d, J = 10.7 Hz, 2H), 2.91(s, 2H), 2.83 (s, 2H), 2.67 (s, 2H), 2.38 (d, J = 37.1 Hz, 3H). 203

397 398 CDCl₃ δ 7.83 (dd, J = 8.7, 5.5 Hz, 2H), 7.36 (d, J = 8.1 Hz,1H), 7.17-7.06 (m, 3H), 6.77 (s, 1H), 4.71 (t, J = 6.6 Hz, 2H), 4.64 (t,J = 6.1 Hz, 2H), 4.59 (s, 2H), 3.85-3.76 (m, 2H), 3.67 (dd, J = 12.5,6.2 Hz, 1H), 3.51-3.42 (m, 2H), 2.99 (s, 2H), 2.69-2.61 (m, 2H), 2.52(d, J = 6.6 Hz, 2H). 204

300 301 δ 9.95 (s, 1H), 7.93 (dd, J = 8.4, 5.8 Hz, 2H), 7.58 (d, J = 8.3Hz, 1H), 7.27-7.11 (m, 3H), 5.12 (s, 2H), 3.44-3.37 (m, 3H), 3.12 (s,2H), 2.16 (s, 3H). 205

348 349 δ 10.10 (s, 1H), 8.32 (s, 1H), 7.70 (s, 1H), 7.57 (d, J = 8.4Hz, 1H), 7.40-7.20 (m, 6H), 6.48 (s, 1H), 5.11 (s, 2H), 3.63-3.39 (m,5H), 3.26 (s, 2H). 206

348 349 δ 9.51 (s, 1H), 7.94 (d, J = 7.6 Hz, 2H), 7.82 (s, 1H), 7.65 (d,J = 8.3 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H),7.25 (d, J = 8.4 Hz, 1H), 5.33 (s, 2H), 4.08 (s, 2H), 3.63 (s, 2H), 2.83(s, 2H), 2.43 (s, 3H). 208

334 335 δ 9.47 (s, 1H), 7.91 (d, J = 7.4 Hz, 2H), 7.77 (s, 1H), 7.63 (d,J = 8.3 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H),7.25 (d, J = 8.4 Hz, 1H), 5.33 (s, 2H), 3.96 (t, J = 5.3 Hz, 2H), 3.90(s, 2H), 3.05 (s, 2H). 210

366 367 δ 9.12 (s, 1H), 8.45 (d, J = 4.5 Hz, 1H), 8.24 (s, 2H), 7.62 (d,J = 8.1 Hz, 1H), 7.39 (dd, J = 7.9, 4.8 Hz, 1H), 7.16 (d, J = 8.2 Hz,1H), 5.21 (s, 2H), 3.46 (s, 2H), 3.27 (s, 2H), 2.53 (d, J = 24.3 Hz,2H), 2.45- 2.33 (m, 2H), 2.29 (s, 3H), 1.74 (s, 2H), 1.58 (s, 4H). 211

366 367 δ 9.12 (d, J = 2.0 Hz, 1H), 8.45 (dd, J = 4.7, 1.5 Hz, 1H),8.29-8.19 (m, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.39 (dd, J = 8.0, 4.7 Hz,1H), 7.16 (d, J = 8.2 Hz, 1H), 5.21 (s, 2H), 3.52- 3.33 (m, 4H), 3.15(d, J = 9.9 Hz, 1H), 2.31 (s, 2H), 2.15 (s, 3H), 2.07- 1.96 (m, 1H),1.84 (d, J = 37.5 Hz, 1H), 1.68 (s, 1H), 1.61-1.38 (m, 3H), 1.31 (s,1H). 212

334 335 δ 8.80 (s, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.59 (s, 1H), 7.55 (d,J = 8.2 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H),7.14 (d, J = 8.2 Hz, 1H), 6.74 (s, 1H), 5.05 (s, 2H), 4.71 (s, 2H), 4.10(t, J = 5.2 Hz, 2H), 3.84 (t, J = 5.2 Hz, 2H). 214

333 334 δ 9.15 (s, 1H), 8.71 (s, 1H), 8.56 (s, 2H), 8.48 (d, J = 3.8 Hz,1H), 8.28 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.43 (dd, J =7.9, 4.7 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 5.33 (s, 2H), 4.85 (s, 4H).215

446 447 CDCl₃ δ 9.09 (s, 1H), 8.55 (d, J = 4.3 Hz, 1H), 8.15 (d, J = 8.2Hz, 1H), 7.46- 7.37 (m, 2H), 7.34-7.31 (m, 2H), 7.16 (d, J = 7.8 Hz,1H), 6.75 (s, 1H), 4.70 (s, 2H), 3.88 (s, 3H), 3.59 (t, J = 6.8 Hz, 2H),3.46 (s, 2H), 3.36 (s, 2H), 2.56 (s, 2H), 2.34 (s, 2H), 1.86 (s, 2H),1.64 (d, J = 24.5 Hz, 4H). 216

338 339 δ 9.11 (d, J = 1.6 Hz, 1H), 8.62 (s, 1H), 8.45 (dd, J = 4.7, 1.6Hz, 1H), 8.28-8.20 (m, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.39 (dd, J = 7.4,4.7 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 5.07 (s, 2H), 4.21 (d, J = 11.8Hz, 1H), 4.07 (d, J = 11.6 Hz, 1H), 2.93 (dt, J = 30.3, 9.8 Hz, 3H),2.58-2.50 (m, 1H), 2.10-1.98 (m, 2H), 1.84 (s, 1H), 1.75 (d, J = 5.6 Hz,1H), 1.67 (d, J = 8.1 Hz, 2H), 1.35-1.21 (m, 1H). 217

338 339 CD₃OD δ 9.08 (s, 1H), 8.44 (d, J = 3.5 Hz, 1H), 8.32 (d, J = 7.8Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.46 (dd, J = 7.8, 4.9 Hz, 1H), 7.28(d, J = 8.1 Hz, 1H), 3.65 (d, J = 7.2 Hz, 4H), 3.59-3.49 (m, 4H),1.94-1.85 (m, 3H), 1.81 (d, J = 5.0 Hz,. 1H). 218

350 351 δ 9.14 (d, J = 1.7 Hz, 1H), 8.63 (s, 1H), 8.48 (dd, J = 4.7, 1.5Hz, 2H), 8.31-8.25 (m, 1H), 7.81 (dd, J = 9.0, 2.4 Hz, 1H), 7.68 (d, J =8.2 Hz, 1H), 7.42 (dd, J = 8.0, 4.8 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H),5.32 (s, 2H), 4.80 (d, J = 17.9 Hz, 4H). 219

335 336 δ 9.56 (s, 1H), 9.13 (d, J = 1.7 Hz, 1H), 8.50 (dd, J = 4.7, 1.6Hz, 1H), 8.31-8.23 (m, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.73 (d, J = 8.3Hz, 1H), 7.43 (dd, J = 7.7, 4.5 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 5.43(s, 2H), 3.99 (t, J = 5.4 Hz, 2H), 3.92 (d, J = 11.7 Hz, 2H), 3.09 (t, J= 5.4 Hz, 2H). 220

338 339 δ 9.13 (d, J = 1.9 Hz, 1H), 8.51 (s, 1H), 8.48 (dd, J = 4.7, 1.5Hz, 1H), 8.29-8.22 (m, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.42 (dd, J = 7.9,4.8 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 5.28 (s, 2H), 3.76 (s, 4H), 3.69(s, 4H), 2.67 (s, 1H), 1.64 (s, 4H). 221

283 284 δ 9.14 (d, J = 1.6 Hz, 1H), 8.48 (dd, J = 4.7, 1.6 Hz, 1H),8.30-8.22 (m, 2H), 7.64 (d, J = 8.2 Hz, 1H), 7.42 (dd, J = 7.6, 4.4 Hz,1H), 7.19 (d, J = 8.2 Hz, 1H), 5.23 (s, 2H), 3.40 (s, 4H), 1.87 (s, 4H).222

489 490 δ 8.20 (s, 1H), 7.97 (dd, J = 8.9, 5.6 Hz, 2H), 7.53 (d, J = 8.2Hz, 1H), 7.24-7.19 (m, 3H), 7.16 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 8.0Hz, 2H), 6.79 (dd, J = 7.4, 1.9 Hz, 1H), 5.10 (s, 2H), 3.46 (q, J = 13.7Hz, 4H), 3.21 (d, J = 10.9 Hz, 1H), 2.49- 2.37 (m, 2H), 2.27 (s, 2H),2.15 (s, 1H), 1.87 (s, 1H), 1.69 (s, 1H), 1.57- 1.46 (m, 3H), 1.38 (s,1H). 223

463 464 δ 8.20 (s, 1H), 7.97 (dd, J = 8.5, 5.7 Hz, 2H), 7.56-7.48 (m,2H), 7.29 (s, 1H), 7.22 (t, J = 8.8 Hz, 2H), 7.16 (d, J = 8.2 Hz, 1H),5.11 (s, 2H), 3.77 (s, 3H), 3.52-3.35 (m, 4H), 3.18 (s, 1H), 2.47-2.38(m, 1H), 2.24 (d, J = 31.9 Hz, 2H), 2.09 (s, 1H), 1.87 (d, J = 31.9 Hz,1H), 1.63 (d, J = 31.9 Hz, 1H), 1.59- 1.40 (m, 3H), 1.33 (s, 1H), 1.23(s, 1H). 224

355 356 δ 8.60 (s, 1H), 7.97 (dd, J = 8.9, 5.6 Hz, 2H), 7.53 (d, J = 8.2Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.16 (d, J = 8.2 Hz, 1H), 4.98 (s,2H), 4.24 (d, J = 11.5 Hz, 1H), 4.09 (d, J = 12.8 Hz, 1H), 3.05-2.84 (m,3H), 2.57 (d, J = 10.7 Hz, 1H), 2.05 (dd, J = 17.8, 9.0 Hz, 2H), 1.86(s, 1H), 1.78 (d, J = 5.4 Hz, 1H), 1.69 (d, J = 8.2 Hz, 2H), 1.39-1.24(m, 1H). 225

159 460 δ 8.69 (s, 1H), 7.96 (dd, J = 8.8, 5.7 Hz, 2H), 7.54 (d, J = 8.2Hz, 1H), 7.27 (dd, J = 15.7, 8.4 Hz, 3H), 7.23- 7.11 (m, 5H), 5.02 (s,2H), 3.71 (d, J = 16.0 Hz, 2H), 3.52 (t, J = 15.3 Hz, 6H), 2.41-2.28 (m,2H), 1.51-1.33 (m, 1H), 1.23 (dd, J = 12.1, 5.8 Hz, 1H). 226

328 329 δ 10.33 (s, 1H), 7.96 (dd, J = 8.4, 5.7 Hz, 2H), 7.82 (s, 1H),7.67 (d, J = 8.3 Hz, 1H), 7.23 (t, J = 9.3 Hz, 3H), 5.32 (s, 2H), 2.55(d, J = 13.6 Hz, 3H). 228

398 399 δ 8.66 (s, 1H), 8.55 (s, 2H), 8.00 (d, J = 8.8 Hz, 2H), 7.60 (d,J = 8.2 Hz, 1H), 7.27 (t, J = 74.0 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H),7.17 (d, J = 8.4 Hz, 1H), 5.22 (s, 2H), 4.85 (s, 4H). 229

356 357 CD₃OD δ 7.80 (dd, J = 8.8, 5.6 Hz, 2H), 7.39 (d, J = 8.2 Hz,1H), 7.17 (d, J = 8.2 Hz, 1H), 7.02 (t, J = 8.8 Hz, 2H), 3.76 (s, 4H),3.62-3.48 (m, 4H), 1.79-1.65 (m, 4H). 230

404 405 CD₃OD δ 7.82 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.2 Hz, 1H), 7.17(d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.7 Hz, 2H), 6.75 (t, J = 74.4 Hz,1H), 3.75 (s, 4H), 3.59 -3.49 (m, 4H), 1.79-1.64 (m, 4H). 231

286 287 δ 8.14 (s, 1H), 8.00 (s, 1H), 7.78 (s, 1H), 7.22 (d, J = 8.1 Hz,1H), 7.09 (d, J = 8.1 Hz, 1H), 4.88 (s, 2H), 3.92-3.77 (s, 3H),3.38-3.35 (s, 4H), 1.86 (s, 4H). 232

348 349 δ 8.21 (s, 1H), 8.02-7.95 (m, 2H), 7.55 (d, J = 8.2 Hz, 1H),7.26 (t, J = 74.0 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.4Hz, 1H), 5.12 (s, 2H), 3.40 (s, 4H), 1.87 (s, 4H). 235

439 440 CD₃CN δ 7.97-7.93 (m, 2H), 7.46-7.44 (m, 1H), 7.18-7.12 (m, 4H),4.64 (br, 2H), 3.87-3.83 (m, 2H), 3.69-3.64 (m, 2H), 3.40-3.28 (m, 4H),2.84 (s, 2H), 2.53-2.46 (m, 4H), 2.26-2.24 (m, 2H), 1.68-1.63 (m, 3H),1.18- 1.13 (m, 2H) 236

425 426 CD₃CN δ 7.98-7.94 (m, 2H), 7.47-7.45 (m, 1H), 7.18-7.13 (m, 4H),4.64 (br, 2H), 3.88-3.85 (m, 2H), 3.68-3.63 (m, 2H), 3.37-3.30 (m, 4H),2.85 (s, 2H), 2.63-2.57 (m, 4H), 2.22-2.16 (m, 1H), 1.95-1.93 (m, 2H),1.48- 1.38 (m, 2H) 237

439 440 CD₃OD δ 7.83 (s, 2H), 7.36-7.34 (d, J = 8.0 Hz, 1H), 7.10-7.07(m, 3H), 6.76 (s, 1H), 3.97-3.96 (t, J = 0.4 Hz, 1H), 3.78-3.70 (m, 5H),3.51- 3.45 (m, 3H), 3.04-3.02 (d, J = 7.6 Hz, 1H), 2.72 (s, 2H), 2.24(s, 3H), 2.13-2.09 (m, 2H), 2.01-1.91 (m, 2H), 1.54-1.47 (m, 2H), 1.26(s, 2H). 238

342 343 CD₃OD δ 7.91 (dd, J = 8.3, 5.6 Hz, 2H), 7.50 (d, J = 8.2 Hz,1H), 7.29 (d, J = 8.2 Hz, 1H), 7.14 (t, J = 8.7 Hz, 2H), 3.77 (d, J =10.3 Hz, 2H), 3.58 (d, J = 9.7 Hz, 2H), 3.50 (d, J = 6.8 Hz, 2H), 1.63(s, 2H), 1.04-0.91 (m, 1H). 239

368 369 δ 10.21 (s, 1H), 8.01-7.90 (m, 2H), 7.59 (d, J = 8.2 Hz, 1H),7.23 (dd, J = 16.9, 8.4 Hz, 3H), 5.09 (s, 2H), 4.55 (t, J = 6.5 Hz, 2H),4.41 (t, J = 5.7 Hz, 2H), 3.75-3.63 (m, 1H), 3.05 (d, J = 8.9 Hz, 2H),2.39 (d, J = 8.7 Hz, 3H), 1.93 (s, 2H). 240

433 434 δ 8.54 (d, J = 10.9 Hz, 2H), 7.98 (dd, J = 8.8, 5.6 Hz, 2H),7.57 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17(d, J = 8.2 Hz, 1H), 5.18 (s, 2H), 4.80 (s, 4H), 3.96 (d, J = 10.9 Hz,2H), 3.51-3.40 (m, 2H), 2.97 (t, J = 11.5 Hz, 1H), 1.78 (dd, J = 10.6,7.4 Hz, 4H). 241

381 382 δ 10.18 (s, 1H), 8.00-7.92 (m, 2H), 7.59 (d, J = 8.3 Hz, 1H),7.22 (dd, J = 17.2, 8.5 Hz, 3H), 5.08 (s, 2H), 3.29 (t, J = 6.7 Hz, 2H),3.17- 3.08 (m, 1H), 2.96 (d, J = 8.9 Hz, 2H), 2.78 (t, J = 6.4 Hz, 2H),2.37 (d, J = 8.5 Hz, 2H), 2.31 (s, 1H), 21.8 (s, 3H), 1.89 (s, 2H). 242

355 356 δ 8.21 (s, 1H), 7.96 (dd, J = 8.8, 5.6 Hz, 2H), 7.53 (d, J = 8.1Hz, 1H), 7.22 (t, J = 8.8 Hz, 2H), 7.15 (d, J = 8.2 Hz, 1H), 5.06 (s,2H), 3.59 (d, J = 10.5 Hz, 2H), 3.41 (d, J = 9.7 Hz, 2H), 2.24 (s, 6H),1.62 (s, 2H), 1.38 (s, 1H). 243

393 394 δ 8.55 (d, J = 8.1 Hz, 2H), 7.98 (dd, J = 8.9, 5.6 Hz, 2H), 7.57(d, J = 8.2 Hz, 1H), 7.44 (s, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17 (d, J= 8.2 Hz, 1H), 5.19 (s, 2H), 4.83 (s, 4H), 4.53 (s, 2H), 3.38 (s, 3H).244

421 422 δ 8.46 (s, 1H), 7.98 (dd, J = 8.9, 5.6 Hz, 2H), 7.57 (d, J = 8.2Hz, 1H), 7.31 (s, 1H), 7.23 (t, J = 8.9 Hz, 2H), 7.16 (s, 1H), 5.16 (s,2H), 4.64 (s, 2H), 4.51 (s, 2H), 4.24 (d, J = 7.4 Hz, 2H), 3.31-3.22 (m,2H), 3.03 (s, 2H), 2.87-2.74 (m, 1H), 2.25 (s, 3H). 245

421 422 δ 8.45 (s, 1H), 7.98 (dd, J = 8.9, 5.6 Hz, 2H), 7.61 (s, 1H),7.56 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17 (d, J = 8.2 Hz,1H), 5.15 (s, 2H), 4.51 (s, 4H), 4.29 (d, J = 7.3 Hz, 2H), 3.24 (t, J =7.2 Hz, 2H), 2.98 (t, J = 6.1 Hz, 2H), 2.80- 2.73 (m, 1H), 2.22 (s, 3H).246

407 408 δ 8.51 (s, 1H), 7.98 (dd, J = 8.8, 5.6 Hz, 2H), 7.57 (d, J = 8.2Hz, 1H), 7.37 (s, 1H), 7.23 (t, J = 8.9 Hz, 2H), 7.17 (d, J = 8.2 Hz,1H), 5.15 (s, 2H), 4.91-4.84 (m, 1H), 4.81- 4.67 (m, 2H), 4.51 (s, 2H),3.69 (t, J = 7.4 Hz, 2H), 3.32-3.23 (m, 2H), 2.32 (s, 3H). 247

407 408 δ 8.47 (s, 1H), 7.98 (dd, J = 8.9, 5.6 Hz, 2H), 7.73 (s, 1H),7.57 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 8.9 Hz, 2H), 7.17 (d, J = 8.2 Hz,1H), 5.16 (s, 2H), 4.99-4.89 (m, 1H), 4.55 (s, 4H), 3.70 (t, J = 7.4 Hz,2H), 3.37 (t, J = 7.4 Hz, 2H), 2.32 (s, 3H). 248

425 426 δ 8.28 (s, 1H), 8.02-7.90 (m, 2H), 7.53 (d, J = 8.2 Hz, 1H),7.38 (t, J = 7.9 Hz, 1H), 7.27-7.18 (m, 2H), 7.18-7.09 (m, 1H), 5.10 (s,2H), 4.67-4.59 (m, 0.5H), 4.52-4.41 (m, 4H), 4.38-4.32 (m, 0.5H), 3.70-3.63 (m, 1H), 3.52-3.47 (m, 2H), 3.38-3.35 (m, 1H), 2.67-2.52 (m, 3H),2.05 (s, 3H), 1.95-1.84 (m, 2H), 1.27-1.19 (m, 2H). 249

417 418 δ 8.59 (s, 1H), 7.99 (dd, J = 8.9, 5.6 Hz, 2H), 7.57 (d, J = 8.2Hz, 1H), 7.25-7.16 (m, 3H), 7.12 (t, J = 7.7 Hz, 1H), 6.64 (d, J = 7.4Hz, 1H), 6.48 (d, J = 8.2 Hz, 1H), 5.16 (s, 2H), 4.98 (s, 2H), 4.68 (s,2H), 3.37 (t, J = 6.8 Hz, 4H), 1.92 (t, J = 6.4 Hz, 4H). 250

434 435 δ 8.53 (s, 1H), 8.38 (d, J = 1.7 Hz, 1H), 7.70 (s, 1H), 7.52 (d,J = 8.2 Hz, 1H), 7.48 (dd, J = 3.6, 1.1 Hz, 1H), 7.41 (dd, J = 5.0, 1.0Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.06 (dd, J = 5.0, 3.6 Hz, 1H), 5.17(s, 2H), 4.74 (s, 4H), 2.87 (d, J = 11.5 Hz, 2H), 2.55 (dd, J = 10.5,6.0 Hz, 1H), 2.12 (s, 3 H), 1.97 (td, J = 11.1, 3.2 Hz, 2H), 1.78-1.62(m, 4H). 251

432 433 δ 8.59-8.52 (m, 2H), 7.85 (d, J = 1.6 Hz, 1H), 7.52 (d, J = 8.2Hz, 1H), 7.48 (dd, J = 3.6, 1.1 Hz, 1H), 7.41 (dd, J = 5.1, 1.0 Hz, 1H),7.12 (d, J = 8.2 Hz, 1H), 7.06 (dd, J = 5.0, 3.6 Hz, 1H), 6.28 (s, 1H),5.18 (s, 2H), 4.77 (s, 4H), 3.05 (s, 2H), 2.60 (t, J = 5.4 Hz, 2H), 2.52(s, 2H), 2.30 (s, 3H). 252

446 447 δ 8.55 (s, 1H), 8.38 (d, J = 1.7 Hz, 1H), 8.02-7.94 (m, 2H),7.70 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17(d, J = 8.2 Hz, 1H), 5.17 (d, J = 8.9 Hz, 2H), 4.75 (s, 4H), 2.89 (d, J= 11.1 Hz, 2H), 2.61-2.53 (m, 1H), 2.21 (s, 3H), 1.99 (t, J = 10.1 Hz,2H), 1.78- 1.63 (m, 4H). 253

444 445 δ 8.57 (d, J = 2.7 Hz, 2H), 7.98 (dd, J = 8.8, 5.6 Hz, 2H), 7.85(s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 8.9 Hz, 2H), 7.17 (d, J= 8.2 Hz, 1H), 6.28 (s, 1H), 5.19 (s, 2H), 4.78 (s, 4H), 3.04 (s, 2H),2.60 (t, J = 5.2 Hz, 2H), 2.52 (s, 2H), 2.30 (s, 3H). 254

404 405 δ 8.09 (d, J = 3.3 Hz, 2H), 7.94- 7.87 (m, 3H), 7.83 (s, 1H),7.23 (t, J = 8.9 Hz, 2H), 6.37 (s, 1H), 5.25 (s, 2H), 4.71 (s, 4H), 3.92(t, J = 7.3 Hz, 4H), 2.36-2.26 (m, 2H). 255

389 390 δ 8.53 (s, 1H), 8.40 (s, 1H), 7.98 (dd, J = 8.9, 5.6 Hz, 2H),7.57 (d, J = 8.2 Hz, 1H), 7.32 (s, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17(d, J = 8.2 Hz, 1H), 5.18 (s, 2H), 4.77 (s, 4H), 2.17- 2.07 (m, 1H),1.00-0.79 (m, 4H). 256

424 425 CDCl₃ δ 7.83 (dd, J = 8.8, 5.4 Hz, 2H), 7.35 (d, J = 8.1 Hz,1H), 7.16-7.06 (m, 3H), 6.75 (s, 1H), 4.59 (s, 2H), 3.82-3.73 (m, 2H),3.47 (s, 2H), 3.40 (d, J = 10.3 Hz, 2H), 2.90 (d, J = 17.3 Hz, 4H), 2.63(d, J = 6.6 Hz, 5H), 2.48 (d, J = 6.4 Hz, 2H), 2.32 (s, 3H). 257

352 353 δ 8.45 (s, 1H), 7.98 (dd, J = 8.8, 5.6 Hz, 2H), 7.57 (d, J = 8.2Hz, 2H), 7.22 (t, J = 8.9 Hz, 2H), 7.17 (d, J = 8.2 Hz, 1H), 5.16 (s,2H), 4.51 (s, 4H), 3.85 (s, 3H). 258

352 353 δ 8.45 (s, 1H), 7.98 (dd, J = 8.7, 5.7 Hz, 2H), 7.57 (d, J = 8.2Hz, 1H), 7.28 (s, 1H), 7.23 (t, J = 8.9 Hz, 2H), 7.17 (d, J = 8.2 Hz,1H), 5.16 (s, 2H), 4.62 (s, 2H), 4.52 (s, 2H), 3.78 (s, 3H). 259

366 367 δ 8.55 (s, 1H), 7.98 (dd, J = 8.9, 5.6 Hz, 2H), 7.57 (d, J = 8.2Hz, 1H), 7.42-7.36 (m, 1H), 7.25-7.13 (m, 5H), 5.19 (s, 2H), 4.84 (s,4H). 260

379 380 δ 8.52 (s, 1H), 8.17 (s, 1H), 7.97 (dd, J = 8.8, 5.6 Hz, 2H),7.57 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.16 (d, J = 8.2 Hz,1H), 6.84 (s, 1H), 5.18 (s, 2H), 4.75 (s, 4H), 3.86 (s, 3H). 261

420 421 δ 8.56 (s, 1H), 8.49 (s, 1H), 7.44 (s, 1H), 7.36 (dd, J = 8.5,6.3 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.13-7.00 (m, 3H), 5.11 (s, 2H),4.80 (s, 4H), 3.56 (s, 2H), 2.34 (s, 3H), 2.21 (s, 6H). 262

397 398 CDCl₃ δ 7.79 (s, 2H), 7.35 (s, 1H), 7.13 (d, J = 8.3 Hz, 3H),4.72 (t, J = 6.5 Hz, 2H), 4.65 (t, J = 6.8 Hz, 2H), 3.92- 3.83 (m, 1H),3.80-3.47 (m, 4H), 2.30 (s, 3H), 1.79 (s, 2H), 1.52-1.48 (m, 1H). 263

409 410 δ 10.17 (s, 1H), 7.95 (dd, J = 8.8, 5.6 Hz, 2H), 7.58 (d, J =8.3 Hz, 1H), 7.22 (dd, J = 17.9, 8.7 Hz, 3H), 5.09 (s, 2H), 3.10 (d, J =8.9 Hz, 2H), 2.68 (d, J = 8.5 Hz, 2H), 2.37 (d, J = 8.6 Hz, 2H), 2.28(s, 1H), 2.12 (s, 3H), 2.00 (t, J = 7.6 Hz, 1H), 1.93-1.80 (m, 4H), 1.73(d, J = 13.4 Hz, 2H), 1.32 (t, J = 13.5 Hz, 2H). 264

396 397 δ 10.17 (s, 1H), 7.96 (dd, J = 8.8, 5.6 Hz, 2H), 7.59 (d, J =8.2 Hz, 1H), 7.22 (dd, J = 17.2, 8.5 Hz, 3H), 5.09 (s, 2H), 3.81 (d, J =11.2 Hz, 2H), 3.28 (t, J = 11.2 Hz, 2H), 3.11 (d, J = 9.0 Hz, 2H), 2.39(d, J = 8.5 Hz, 2H), 2.34-2.21 (m, 2H), 1.91 (s, 2H), 1.71 (d, J = 12.2Hz, 2H), 1.30 (dd, J = 23.6, 13.4 Hz, 2H). 265

429 430 δ 9.15 (s, 1H), 8.59 (s, 1H), 8.48 (d, J = 3.6 Hz, 1H), 8.38 (s,1H), 8.28 (d, J = 7.8 Hz, 1H), 7.70-7.67 (m, 2H), 7.42 (dd, J = 7.7, 4.6Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 5.30 (s, 2H), 4.77 (s, 4H), 2.87 (d,J = 10.9 Hz, 2H), 2.55 (s, 1H), 2.20 (s, 3H), 1.99-1.94 (m, 2H),1.75-1.69 (m, 4H). 266

454 455 δ 8.55 (s, 1H), 8.52 (s, 1H), 8.01- 7.94 (m, 2H), 7.57 (d, J =8.2 Hz, 1H), 7.42 (s, 1H), 7.26-7.19 (m, 2H), 7.17 (d, J = 8.2 Hz, 1H),5.18 (s, 2H), 4.81 (s, 4H), 3.87 (s, 2H), 3.70 (t, J = 12.5 Hz, 4H). 267

383 384 δ 8.18 (s, 1H), 7.99-7.92 (m, 2H), 7.53 (d, J = 8.2 Hz, 1H),7.22 (t, J = 8.9 Hz, 2H), 7.14 (d, J = 8.2 Hz, 1H), 5.06 (s, 2H),4.66-4.60 (m, 2H), 4.37 (t, J = 6.3 Hz, 2H), 3.97- 3.89 (m, 1H), 3.58(d, J = 10.6 Hz, 2H), 3.40 (d, J = 10.2 Hz, 2H), 1.87 (s, 1H), 1.54 (s,2H), 1.23 (s, 1H). 268

395 396 δ 10.20 (s, 1H), 8.01-7.91 (m, 2H), 7.58 (d, J = 8.2 Hz, 1H),7.25- (m, 3H), 5.08 (s, 2H), 3.30-3.21 (m, 2H), 2.98 (d, J = 9.9 Hz,2H), 2.69 (t, J = 6.3 Hz, 2H), 2.54 (t, J = 7.8 Hz, 2H), 2.46-2.37 (m,1H), 2.32 (t, J = 8.8 Hz, 3H), 2.15 (s, 3H), 1.86 (s, 2H). 269

424 425 CDCl₃ δ 7.90-7.77 (m, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.10 (dd, J= 15.9, 8.4 Hz, 3H), 6.73 (s, 1H), 4.54 (s, 2H), 3.75 (d, J = 9.5 Hz,2H), 3.60 (d, J = 9.3 Hz, 2H), 2.51 (s, 7H), 2.36 (d, J = 6.6 Hz, 2H),2.31 (s, 4H), 1.51 (s, 2H), 0.87 (m, 1H) 270

381 382 CDCl₃ δ 7.82 (dd, J = 8.6, 5.5 Hz, 2H), 7.35 (d, J = 8.1 Hz,1H), 7.10 (dd, J = 16.2, 7.9 Hz, 3H), 6.72 (s, 1H), 4.54 (s, 2H), 3.72(d, J = 9.2 Hz, 2H), 3.59 (d, J = 9.3 Hz, 2H), 3.30 (t, J = 7.0 Hz, 4H),2.40 (d, J = 6.8 Hz, 2H), 2.14 (p, J = 7.1 Hz, 2H), 1.54 (s, 2H),0.85-0.70 (m, 1H). 271

454 455 δ 8.56 (s, 1H), 8.41 (s, 1H), 8.01- 7.94 (m, 2H), 7.74 (s, 1H),7.57 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17 (d, J = 8.2 Hz,1H), 5.18 (s, 2H), 4.78 (s, 4H), 3.78 (s, 2H), 3.63 (t, J = 12.5 Hz,4H). 272

418 419 δ 8.55 (s, 1H), 8.36 (s, 1H), 8.02- 7.94 (m, 2H), 7.69 (s, 1H),7.57 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17 (d, J = 8.2 Hz,1H), 5.18 (s, 2H), 4.77 (s, 4H), 3.58 (s, 2H), 3.16 (t, J = 6.0 Hz, 4H),2.04-1.95 (m, 2H). 273

468 469 δ 8.56 (s, 1H), 8.41 (s, 1H), 8.02- 7.95 (m, 2H), 7.74 (s, 1H),7.57 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 7.17 (d, J = 8.2 Hz,1H), 5.18 (s, 2H), 4.79 (s, 4H), 3.68 (s, 2H), 2.89 (t, J = 13.3 Hz,2H), 2.71 (t, J = 6.9 Hz, 2H), 2.34-2.19 (m, 2H). 274

405 406 CDCl₃ δ 8.33 (s, 1H), 7.87-7.64 (m, 2H), 7.46-7.36 (m, 2H),7.21-7.06 (m, 3H), 6.96-6.65 (m, 1H), 5.00- 4.83 (m, 4H), 4.58 (s, 2H),2.52 (d, J = 7.0 Hz, 2H), 1.95-1.82 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H).275

436 437 δ 8.56 (s, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.02-7.94 (m, 2H),7.70 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.27- 7.19 (m, 2H), 7.17 (d, J =8.2 Hz, 1H), 5.29-5.07 (m, 3H), 4.78 (s, 4H), 3.67 (s, 2H), 3.61-3.49(m, 2H), 3.23-3.17 (m, 1H), 3.16- 3.10 (m, 1H). 276

356 357 δ 8.24 (s, 1H), 8.02-7.92 (m, 2H), 7.53 (d, J = 8.2 Hz, 1H),7.22 (t, J = 8.9 Hz, 2H), 7.15 (d, J = 8.2 Hz, 1H), 5.07 (s, 2H), 3.66(d, J = 10.5 Hz, 2H), 3.42 (d, J = 10.1 Hz, 2H), 3.25 (d, J = 7.6 Hz,5H), 1.53 (s, 2H), 0.90-0.85 (m, 1H). 277

350 351 δ 9.12 (s, 1H), 8.84 (s, 1H), 8.63 (s, 1H), 8.02-7.95 (m, 2H),7.58 (d, J = 8.2 Hz, 1H), 7.23 (t, J = 8.9 Hz, 2H), 7.17 (d, J = 8.2 Hz,1H), 5.19 (s, 2H), 4.83 (d, J = 7.4 Hz, 4H). Comopunds 127, 138, 180,200, 202, 207, 209, 213, 227, 233, and 234 were intentionally omitted.

TABLE 3 Exemplary Compounds MS MS No. Structure Calc. found ¹H NMR Data(400 MHz, DMSO-d₆) 350

349 350 δ 8.83 (s, 1H), 7.75 (s, 1H), 7.65 (d, J = 7.60 Hz, 2H), 7.43(t, J = 8.40 Hz, 2H), 7.31-7.24 (m, 3H), 7.16 (t, J = 7.20 Hz, 1H), 5.22(t, J = 5.60 Hz, 1H), 4.75 (s, 4H), 4.52 (d, J = 5.60 Hz, 2H), 4.26 (s,2H). 351

376 377 δ 8.79 (s, 1H), 7.72 (d, J = 2.80 Hz, 1H), 7.64 (d, J = 1.20 Hz,2H), 7.41 (t, J = 0.80 Hz, 2H), 7.28 (t, J = 5.60 Hz, 2H), 7.17 (d, J =1.20 Hz, 1H), 7.14 (t, J = 0.80 Hz, 1H), 4.74 (s, 4H), 4.05 (s, 2H),3.39 (s, 2H), 2.15 (s, 6H). 352

417 418 δ 8.79 (s, 1H), 7.73 (s, 1H), 7.65 (d, J = 7.88 Hz, 2H), 7.43(t, J = 8.16 Hz, 2H), 7.20-7.14 (m, 2H), 6.91 (d, J = 6.40 Hz, 2H),4.69-4.66 (m, 1H), 4.06 (s, 2H), 3.14-3.12 (m, 4H), 2.47-2.46 (m, 4H),2.23 (s, 3H). 353

431 432 δ 8.81 (s, 1H), 7.73 (s, 1H), 7.65 (d, J = 8.80 Hz, 2H), 7.42(t, J = Hz, 2H), 7.27 (m, 3H), 7.18-7.12 (m, 1H), 4.74 (s, 4H), 4.05 (s,2H), 3.47 (s, 2H), 2.68 (s, 3H), 2.37 (s, 5H), 2.16 (s, 3H). 354

299 300 1H-NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 7.72 (s, 1H), 7.61(d, J = 7.60 Hz, 2H), 7.41 (t, J = 8.40 Hz, 2H), 7.16 (t, J = 7.20 Hz,1H), 4.01 (s, 2H), 2.79 (d, J = 11.20 Hz, 2H), 2.15 (s, 3H), 1.89-1.82(m, 3H), 1.74 (d, J = 10.00 Hz, 2H), 1.69-1.62 (m, 2H). 356

342 343 δ 8.90 (s, 1H), 7.69 (s, 1H), 7.61 (d, J = 7.60 Hz, 2H), 7.40(t, J = 8.00 Hz, 2H), 7.14 (t, J = 7.60 Hz, 1H), 4.54 (t, J = 6.40 Hz,2H), 4.45 (t, J = 6.00 Hz, 2H), 3.94 (s, 2H), 3.48 (s, 4H), 3.42 (t, J =6.00 Hz, 1H), 2.26 (s, 4H). 357

285 286 δ 10.26 (s, 1H), 7.74 (s, 1H), 7.63 (d, J = 7.60 Hz, 2H), 7.42(t, J = 7.60 Hz, 2H), 7.19 (d, J = 6.40 Hz, 1H), 4.04 (s, 1H), 3.13 (d,J = 10.80 Hz, 2H), 1.89 (s, 2H), 1.82 (d, J = 12.40 Hz, 2H), 1.65 (d, J= 13.20 Hz, 2H). 358

327 328 δ 10.28 (s, 1H), 7.74 (s, 1H), 7.63 (d, J = 8.00 Hz, 2H), 7.42(t, J = 8.40 Hz, 2H), 7.18 (t, J = 7.60 Hz, 1H), 4.38 (d, J = 12.80 Hz,1H), 4.02 (s, 1H), 3.86 (d, J = 14.00 Hz, 1H), 3.07 (t, J = 10.80 Hz,1H), 2.67-2.64 (m, 3H), 2.01 (s, 3H), 1.82 (t, J = 14.80 Hz, 2H), 1.59(d, J = 11.60 Hz, 1H), 1.44 (d, J = 12.40 Hz, 1H). 359

341 342 δ 10.20 (s, 1H), 7.72 (s, 1H), 7.62 (d, J = 8.00 Hz, 2H), 7.41(t, J = 7.60 Hz, 2H), 7.16 (t, J = 7.60 Hz, 1H), 4.52 (t, J = 6.40 Hz,2H), 4.42 (t, J = 6.00 Hz, 2H), 4.02 (s, 2H), 3.37 (t, J = 5.60 Hz, 1H),2.73 (d, J = 11.20 Hz, 1H), 2.45-2.41 (m, 2H), 1.77 (t, J = 10.80 Hz,4H), 1.69- 1.63 (m, 2H). 360

328 329 δ 8.98 (s, 1H), 7.70 (s, 1H), 7.61 (d, J = 8.40 Hz, 2H), 7.40(t, J = 8.00 Hz, 2H), 7.15 (t, J = 8.00 Hz, 1H), 3.49 (s, 2H), 3.47-3.44(m, 8H), 2.03 (s, 3H). 361

300 301 δ 8.88 (s, 1H), 7.69 (s, 1H), 7.61 (d, J = 8.40 Hz, 2H), 7.40(t, J = 8.00 Hz, 2H), 7.14 (t, J = 7.60 Hz, 1H), 3.94 (s, 2H), 3.45 (s,4H), 2.31 (s, 4H), 2.20 (s, 3H). 362

443 444 δ 8.48 (m, 1H), 7.99 (d, J = 5.60 Hz, 2H), 7.57 (td, J = 8.40,Hz, 1H), 7.41 (dt, J = 5.60, Hz, 2H), 7.32 (s, 1H), 7.21 (s, 3H), 6.18(s, 1H), 5.18 (s, 2H), 4.79 (s, 4H), 3.02 (d, J = 2.80 Hz, 2H), 2.29 (s,3H). 363

461 462 δ 8.48 (s, 1H), 7.99 (q, J = 5.72 Hz, 2H), 7.57 (d, J = 8.16 Hz,1H), 7.31- 7.17 (m, 6H), 5.18 (s, 2H), 4.79 (s, 4H), 3.90-3.87 (m, 1H),3.58 (s, 1H), 3.16 (s, 3H), 2.69-2.65 (m, 1H), 2.55 (d, J = 6.88 Hz,1H), 2.44- 2.40 (m, 3H), 2.02-1.97 (m, 1H), 1.66 (t, J = 3.36 Hz, 1H).364

336 337 δ 8.49 (s, 1H), 7.97 (q, J = 2.00 Hz, 2H), 7.57 (d, J = 8.40 Hz,1H), 7.24 (t, J = 6.80 Hz, 2H), 7.16 (d, J = 8.00 Hz, 1H), 5.14 (s, 2H),3.85 (t, J = 13.20 Hz, 2H), 3.65 (t, J = 7.60 Hz, 2H), 2.46 (t, J = 7.20Hz, 2H). 365

377 378 δ 8.53 (s, 1H), 7.68 (t, J = 1.20 Hz, 1H), 7.38 (d, J = 8.00 Hz,1H), 7.29 (t, J = 6.40 Hz, 2H), 7.23 (d, J = 8.00 Hz, 1H), 7.14 (d, J =8.40 Hz, 1H), 6.74 (d, J = 3.20 Hz, 1H), 6.56 (q, J = 1.60 Hz, 1H), 5.20(s, 2H), 4.77 (s, 4H), 3.41 (s, 2H), 2.16 (s, 6H). 366

378 379 δ 8.47 (s, 1H), 7.99 (q, J = 5.72 Hz, 2H), 7.58 (d, J = 8.32 Hz,1H), 7.58 (s, 2H), 7.27-7.17 (m, 4H), 5.24- 5.19 (m, 3H), 4.79 (s, 4H),4.53 (d, J = 5.40 Hz, 2H). 367

460 461 δ 8.47 (s, 1H), 7.99 (q, J = 5.72 Hz, 2H), 7.57 (d, J = 8.24 Hz,1H), 7.32- 7.17 (m, 6H), 5.18 (s, 2H), 4.78 (s, 4H), 3.60 (s, 2H),2.37-2.18 (m, 8H), 2.34 (s, 3H). 368

411 412 δ 9.98 (s, 1H), 7.97 (q, J = 6.00 Hz, 2H), 7.61 (d, J = 8.40 Hz,1H), 7.26- 7.21 (m, 3H), 5.05 (s, 2H), 2.92 (d, J = 11.20 Hz, 2H), 2.79(d, J = 11.60 Hz, 2H), 2.17-2.11 (m, 5H), 1.91 (s, 2H), 1.84 (t, J =12.40 Hz, 4H), 1.68-1.62 (m, 4H), 1.46-1.43 (m, 2H). 369

321 322 δ 8.63 (d, J = 5.88 Hz, 2H), 8.51 (d, J = 4.64 Hz, 1H), 8.35 (s,1H), 7.70 (s, 1H), 7.54 (d, J = 7.76 Hz, 1H), 7.45 (d, J = 5.00 Hz, 1H),7.29 (d, J = 8.52 Hz, 1H), 6.48 (s, 1H), 5.15 (s, 2H), 4.85 (s, 4H). 370

394 395 δ 10.05 (s, 1H), 8.31 (d, J = 2.40 Hz, 1H), 7.69 (s, 1H), 7.56(d, J = 8.40 Hz, 1H), 7.43 (t, J = 6.00 Hz, 1H), 7.33 (t, J = 5.20 Hz,2H), 7.21- 7.15 (m, 2H), 6.48 (t, J = 2.40 Hz, 1H), 4.99 (s, 2H), 3.54(s, 2H), 2.88 (d, J = 11.20 Hz, 2H), 2.01 (t, J = 10.00 Hz, 2H), 1.82(d, J = 11.60 Hz, 2H), 1.69-1.65 (m, 2H). 371

405 406 δ 8.48 (s, 1H), 8.01-7.97 (m, 2H), 7.57 (dd, J = 2.04, 8.18 Hz,1H), 7.32-7.17 (m, 6H), 5.18 (s, 2H), 4.79 (s, 4H), 3.41 (s, 2H), 2.16(s, 6H). 372

321 322 δ 8.62 (s, 2H), 8.51 (d, J = 5.04 Hz, 1H), 7.68 (t, J = 0.84 Hz,1H), 7.44 (d, J = 4.84 Hz, 1H), 7.39 (d, J = 8.16 Hz, 1H), 7.14 (d, J =8.24 Hz, 1H), 6.74 (d, J = 3.32 Hz, 1H), 6.56 (q, J = 1.76 Hz, 1H), 5.21(s, 2H), 4.83 (s, 4H). 373

349 350 δ 8.62 (s, 1H), 8.56 (s, 1H), 8.51 (d, J = 5.08 Hz, 1H), 7.99(q, J = 5.64 Hz, 2H), 7.58 (d, J = 8.24 Hz, 1H), 7.45 (s, 1H), 7.23 (t,J = 8.96 Hz, 2H), 7.17 (d, J = 8.28 Hz, 1H), 5.19 (s, 2H), 4.85 (s, 4H)374

446 447 δ 8.44 (s, 1H), 7.99 (q, J = 5.64 Hz, 2H), 7.57 (d, J = 8.24 Hz,1H), 7.25- 7.17 (m, 4H), 6.92 (d, J = 6.56 Hz, 2H), 5.17 (s, 2H), 4.71(s, 4H), 3.34 (s, 4H), 3.14 (s, 4H), 2.25 (s, 3H) 375

341 342 (MeOD) δ 9.10 (s, 1H), 8.48 (d, J = 4.32 Hz, 1H), 8.35 (d, J =8.08 Hz, 1H), 7.65 (d, J = 8.28 Hz, 1H), 7.49 (q, J = 4.88 Hz, 1H), 7.31(d, J = 8.24 Hz, 1H), 4.10 (d, J = 6.00 Hz, 2H), 3.13 (d, J = 12.40 Hz,2H), 2.49 (s, 3H), 2.40 (t, J = 10.40 Hz, 2H), 1.96-1.86 (m, 3H), 1.47(t, J = 16.00 Hz, 2H). 376

314 315 δ 10.04 (s, 1H), 7.95 (q, J = 5.60 Hz, 2H), 7.59 (d, J = 8.40Hz, 1H), 7.25-7.18 (m, 3H), 5.15 (s, 2H), 2.87-2.85 (m, 2H), 2.45 (m,2H), 2.18 (s, 3H), 1.89 (s, 3H). 377

387 388 (MeOH) δ 8.53-8.51 (m, 1H), 8.05- 7.75 (m, 3H), 7.60 (d, J =8.00 Hz, 2H), 7.41-7.30 (m, 5H), 3.79 (s, 2H), 3.11 (d, J = 11.60 Hz,2H), 2.62 (s, 1H), 2.36 (t, J = 9.60 Hz, 2H), 2.03-1.91 (m, 4H) 378

405 406 δ 10.02 (s, 1H), 9.12 (d, J = 2.00 Hz, 1H), 8.50 (dd, J = 1.60,4.80 Hz, 1H), 8.26 (dd, J = 2.00, 5.00 Hz, 1H), 7.71 (d, J = 8.40 Hz,1H), 7.44 (t, J = 2.40 Hz, 2H), 7.42 (m, 1H), 7.31 (d, J = 1.60 Hz, 1H),7.23 (q, J = 6.40 Hz, 2H), 5.16 (s, 2H), 3.54 (s, 2H), 2.89 (d, J =11.60 Hz, 2H), 2.02 (t, J = 9.60 Hz, 2H), 1.91 (s, 1H), 1.83 (d, J =10.80 Hz, 2H), 1.73-1.67 (m, 2H). 379

404 405 δ 10.01 (s, 1H), 7.93 (d, J = 7.00 Hz, 2H), 7.63 (d, J = 8.32Hz, 1H), 7.45-7.39 (m, 3H), 7.34-7.28 (m, 2H), 7.24-7.15 (m, 3H), 5.05(s, 2H), 3.54 (s, 2H), 2.89 (d, J = 11.60 Hz, 2H), 2.51 (s, 1H), 2.02(t, J = 10.76 Hz, 2H), 1.83 (d, J = 13.16 Hz, 2H), 1.69 (d, J = 11.52Hz, 2H). 380

338 339 δ 7.94 (t, J = 7.20 Hz, 2H), 7.63 (d, J = 8.40 Hz, 1H), 7.42 (t,J = 8.00 Hz, 2H), 7.30 (t, J = 7.20 Hz, 1H), 7.23 (d, J = 8.00 Hz, 1H),5.06 (s, 2H), 4.40 (d, J = 13.60 Hz, 1H), 3.88 (d, J = 13.20 Hz, 1H),3.07 (t, J = 12.00 Hz, 1H), 2.89-2.74 (m, 1H), 2.63-2.51 (m, 2H), 2.02(s, 3H), 1.88 (t, J = 12.80 Hz, 2H), 1.62 (d, J = 11.60 Hz, 1H), 1.49(d, J = 4.00 Hz, 1H). 381

352 353 δ 10.02 (s, 1H), 7.93 (d, J = 7.60 Hz, 2H), 7.63 (d, J = 8.40Hz, 1H), 7.41 (t, J = 8.00 Hz, 2H), 7.31 (d, J = 7.60 Hz, 1H), 7.23 (d,J = 8.40 Hz, 1H), 5.06 (s, 1H), 4.68-4.61 (m, 2H), 4.53 (t, J = 6.40 Hz,2H), 4.43 (t, J = 6.00 Hz, 2H), 4.35 (t, J = 6.40 Hz, 1H), 2.76 (d, J =8.40 Hz, 2H), 1.86-1.67 (m, 6H). 382

313 314 δ 8.61 (s, 1H), 7.68 (s, 1H), 7.61 (d, J = 0.80 Hz, 2H), 7.39(t, J = 0.40 Hz, 2H), 7.14 (t, J = 7.60 Hz, 1H), 3.99 (s, 2H), 3.82-3.79(m, 2H), 3.60-3.56 (m, 2H), 3.54-3.51 (m, 2H), 3.35 (s, 2H), 2.93 (s,2H). 383

416 417 δ 8.81 (s, 1H), 7.73 (s, 1H), 7.65 (d, J = 8.08 Hz, 2H), 7.43(t, J = 7.80 Hz, 2H), 7.29-7.14 (m, 4H), 4.73 (s, 4H), 4.06 (s, 2H),2.87 (d, J = 11.32 Hz, 2H), 2.20 (s, 3H), 1.96-1.91 (m, 2H), 1.72-1.68(m, 4H). 384

311 312 δ 8.55 (s, 1H), 7.70 (s, 1H), 7.62 (d, J = 8.16 Hz, 2H), 7.41(t, J = 7.84 Hz, 2H), 7.15 (t, J = 7.44 Hz, 1H), 4.02 (s, 2H), 3.58 (q,J = 8.00 Hz, 2H), 3.19 (dd, J = 3.48, 10.94 Hz, 2H), 2.68-2.65 (m, 2H),1.80-0.71 (m, 3H), 1.58-1.57 (m, 1H), 1.45- 1.41 (m, 2H). 385

340 341 δ 8.21 (s, 1H), 7.96 (q, J = 2.00 Hz, 2H), 7.53 (d, J = 8.40 Hz,1H), 7.24- 7.15 (m, 3H), 5.08 (s, 2H), 3.48 (d, J = 20.00 Hz, 2H), 3.22(d, J = 16.80 Hz, 2H), 2.67 (s, 2H), 1.80- 1.75 (m, 3H), 1.73-1.70 (m,1H), 1.48-1.44 (m, 2H). 386

467 468 δ 8.49 (s, 1H), 8.01-7.98 (m, 2H), 7.58 (d, J = 8.16 Hz, 1H),7.32 (t, J = 7.36 Hz, 2H), 7.27-7.17 (m, 4H), 5.18 (s, 2H), 4.79 (s,4H), 3.65 (s, 2H), 2.87 (t, J = 13.36 Hz, 2H), 2.70 (t, J = 6.92 Hz,2H), 2.34-0.28 (m, 2H). 387

445 446 δ 8.46 (s, 1H), 7.99 (q, J = 5.60 Hz, 2H), 7.57 (d, J = 8.40 Hz,1H), 7.29- 7.17 (m, 6H), 5.17 (s, 2H), 4.76 (s, 4H), 2.87 (d, J = 11.20Hz, 2H), 2.20 (s, 3H), 1.96 (q, J = 8.40 Hz, 2H), 1.89 (s, 1H),1.72-1.65 (m, 4H). 388

330 331 δ 8.28 (s, 1H), 7.98 (q, J = 2.00 Hz, 2H), 7.54 (d, J = 8.00 Hz,1H), 7.25- 7.16 (m, 3H), 5.11 (s, 2H), 4.00 (s, 1H), 3.50 (s, 3H), 3.34(s, 1H), 3.17 (s, 3H), 1.99 (s, 2H). 389

344 345 δ 8.56 (s, 1H), 8.00-7.96 (m, 2H), 7.54 (dd, J = 1.20, 8.00 Hz,1H), 7.25-7.17 (m, 3H), 5.11 (s, 2H), 4.11 (s, 1H), 3.48-3.33 (m, 7H),1.95-1.77 (m, 4H). 390

368 369 δ 8.43 (s, 1H), 7.99-7.96 (m, 2H), 7.56 (d, J = 8.40 Hz, 1H),7.25-7.16 (m, 3H), 5.11 (s, 2H), 3.72 (q, J = 8.40 Hz, 1H), 3.59-3.48(m, 3H), 3.32 (s, 1H), 2.22-2.21 (m, 1H), 2.06-2.03 (m, 1H). 391

447 448 (MeOD): δ 7.93 (t, J = 5.04 Hz, 2H), 7.56 (t, J = 11.36 Hz, 2H),7.32 (d, J = 8.16 Hz, 1H), 7.15 (t, J = 8.72 Hz, 2H), 6.80 (s, 1H), 4.76(d, J = 16.04 Hz, 4H), 3.61 (s, 4H), 2.61 (t, J = 4.76 Hz, 4H) 2.39 (s,3H). 392

342 343 δ 8.31 (s, 1H), 7.97 (q, J = 6.00 Hz, 2H), 7.53 (d, J = 8.40 Hz,1H), 7.24- 7.14 (m, 3H), 5.08 (s, 2H), 3.81 (q, J = 6.80 Hz, 2H),3.64-3.54 (m, 4H), 3.38 (d, J = 2.40 Hz, 2H), 2.94 (d, J = 2.40 Hz, 2H).393

375 376 δ 9.15 (s, 1H), 8.53-8.48 (m, 2H), 8.29 (d, J = 7.92 Hz, 1H),7.68 (d, J = 8.12 Hz, 1H), 7.45-7.42 (m, 1H), 7.34 (t, J = 6.96 Hz, 2H),7.27 (d, J = 8.00 Hz, 1H), 7.21 (d, J = 8.16 Hz, 1H), 5.31 (s, 2H), 4.80(s, 4H), 4.44 (s, 2H), 3.31 (s, 3H). 394

392 393 δ 8.48 (s, 1H), 6.24 (q, J = 2805.60 Hz, 2H), 7.58 (d, J = 8.12Hz, 1H), 7.34-7.17 (m, 6H), 5.18 (s, 3H), 4.77 (s, 5H), 1.34 (d, J =6.36 Hz, 3H). 395

361 362 δ 9.15 (d, J = 2.00 Hz, 1H), 8.50- 8.47 (m, 2H), 8.28 (d, J =8.00 Hz, 1H), 7.67 (d, J = 8.40 Hz, 1H), 7.42 (q, J = 4.40 Hz, 1H), 7.31(d, J = 2.80 Hz, 2H), 7.26 (d, J = 8.00 Hz, 1H), 7.20 (d, J = 8.00 Hz,1H), 5.30 (s, 2H), 5.22 (t, J = 5.60 Hz, 1H), 4.79 (s, 4H), 4.53 (d, J =5.60 Hz, 2H). 396

392 393 δ 8.49 (s, 1H), 7.99 (q, J = 5.64 Hz, 2H), 7.58 (d, J = 8.16 Hz,1H), 7.34 (t, J = 7.00 Hz, 2H), 7.28-7.17 (m, 4H), 5.19 (s, 2H), 4.80(s, 4H), 4.44 (s, 2H), 3.31 (s, 3H). 397

349 350 δ 8.58 (s, 1H), 8.49 (d, J = 4.80 Hz, 1H), 7.99 (q, J = 6.00 Hz,2H), 7.82 (d, J = 7.60 Hz, 1H), 7.59 (d, J = 8.40 Hz, 1H), 7.34 (q, J =4.80 Hz, 1H), 7.23 (t, J = 8.80 Hz, 2H), 7.18 (d, J = 8.40 Hz, 1H), 5.20(s, 2H), 4.81 (s, 4H). 398

433 434 δ 8.45 (s, 1H), 7.53-7.49 (m, 2H), 7.42 (d, J = 4.72 Hz, 1H),7.30-7.25 (m, 3H), 7.13 (d, J = 8.04 Hz, 1H), 7.07 (s, 1H), 5.16 (s,2H), 4.77 (s, 4H), 3.22 (d, J = 6.04 Hz, 1H), 2.32 (d, J = 8.96 Hz, 2H),1.91 (s, 1H), 1.68 (s, 4H), 1.31 (d, J = 6.04 Hz, 3H). 399

445 446 (MeOD): δ 7.92 (q, J = 5.60 Hz, 2H), 7.53 (d, J = 8.00 Hz, 1H),7.39- 7.31 (m, 4H), 7.14 (t, J = 8.80 Hz, 2H), 4.87-4.92 (m, 4H),3.50-3.49 (m, 1H), 2.76 (s, 2H), 2.54 (s, 2H), 1.89-1.84 (m, 4H), 1.50(d, J = 6.80 Hz, 3H). 400

455 456 δ 8.45 (s, 1H), 7.53-7.48 (m, 2H), 7.41 (d, J = 0.80 Hz, 1H),7.32 (t, J = 7.20 Hz, 2H), 7.25 (d, J = 7.60 Hz, 1H), 7.13 (d, J = 8.00Hz, 1H), 7.07 (t, J = 1.20 Hz, 1H), 5.16 (s, 2H), 4.78 (s, 4H), 3.65 (s,2H), 2.87 (t, J = 13.20 Hz, 2H), 2.70 (t, J = 7.20 Hz, 2H), 2.28-2.22(m, 2H). 401

427 428 δ 8.44 (s, 1H), 7.52 (d, J = 8.00 Hz, 1H), 7.35 (d, J = 4.00 Hz,1H), 7.29 (t, J = 6.40 Hz, 2H), 7.23 (d, J = 8.00 Hz, 1H), 7.12 (d, J =8.00 Hz, 1H), 7.06 (d, J = 3.60 Hz, 1H), 5.26 (s, 2H), 4.77 (s, 4H),3.40 (s, 2H), 2.15 (s, 6H). 402

394 395 δ 8.80 (s, 1H), 7.71-7.66 (m, 3H), 7.31-7.22 (m, 5H), 4.75 (s,4H), 4.06 (s, 2H), 3.40 (s, 2H), 2.16 (s, 6H). 403

432 433 δ 8.47 (s, 1H), 8.01-7.97 (m, 2H), 7.57 (d, J = 8.00 Hz, 1H),7.29-7.17 (m, 6H), 5.17 (s, 2H), 4.77 (s, 4H), 3.96 (d, J = 10.80 Hz,2H), 3.48- 3.41 (m, 2H), 2.81 (m, 1H), 1.72- 1.67 (m, 4H). 404

370 371 (MeOD): δ 8.20 (s, 1H), 7.97 (q, J = 6.00 Hz, 2H), 7.53 (d, J =8.40 Hz, 1H), 7.24-7.15 (m, 2H), 5.10 (s, 2H), 3.64 (s, 2H), 3.55-3.51(m, 2H), 3.51-3.32 (m, 2H), 1.81 (t, J = 6.80 Hz, 2H), 1.53 (t, J = 5.20Hz, 4H). 405

431 432 δ 8.45 (s, 1H), 7.98 (q, J = 5.60 Hz, 2H), 7.56 (d, J = 8.40 Hz,1H), 7.30- 7.16 (m, 6H), 5.17 (s, 2H), 4.77 (s, 4H), 3.58 (s, 2H), 2.43(s, 4H), 1.69 (s, 4H). 406

341 342 δ 9.98 (s, 1H), 7.98-7.95 (m, 2H), 7.61 (d, J = 8.00 Hz, 1H),7.26-7.21 (m, 3H), 5.05 (s, 2H), 4.35 (s, 2H), 3.05 (s, 1H), 1.84-1.64(m, 6H), 1.62 (dd, J = 4.80, 12.60 Hz, 2H). 407

341 342 (MeOD): δ 7.74 (s, 1H), 7.63 (d, J = 8.00 Hz, 2H), 7.43 (t, J =7.20 Hz, 2H), 7.23 (t, J = 6.40 Hz, 1H), 3.77 (m, 2H), 3.70 (m, 2H),3.59 (m, 2H), 3.44 (s, 2H), 1.95 (t, J = 10.00 Hz, 2H), 1.66 (t, J =4.80 Hz, 4H). 408

499 500 δ 8.45 (s, 1H), 7.98 (q, J = 6.00 Hz, 2H), 7.56 (d, J = 8.40 Hz,1H), 7.32- 7.29 (m, 2H), 7.26-7.16 (m, 4H), 5.16 (s, 2H), 4.78 (s, 4H),3.61 (q, J = 13.20 Hz, 2H), 3.06 (s, 1H), 2.72 (t, J = 9.20 Hz, 1H),2.55-2.54 (m, 2H), 2.06-1.98 (m, 1H), 1.82-1.73 (m, 1H). 409

393 394 δ 8.43 (s, 1H), 7.51-7.48 (m, 2H), 7.41 (d, J = 1.20 Hz, 1H),7.30-7.28 (m, 2H), 7.25 (d, J = 15.60 Hz, 1H), 7.12 (d, J = 8.00 Hz,1H), 7.07-7.05 (m, 1H), 5.15 (s, 2H), 4.77 (s, 4H), 3.39 (s, 2H), 2.14(s, 6H). 410

419 420 δ 8.44 (s, 1H), 7.50 (dd, J = 3.60, 11.60 Hz, 2H), 7.42 (d, J =6.80 Hz, 1H), 7.29-7.25 (m 3H), 7.17 (d, J = 20.00 Hz, 1H), 7.13-7.12(m, 1H), 5.16 (s, 2H), 4.77 (s, 4H), 3.59 (s, 2H), 2.43 (s, 4H), 1.70(s, 4H). 411

432 433 δ 8.56 (s, 1H), 8.02-7.97 (m, 2H), 7.78-7.76 (m, 1H), 7.59 (dd,J = 3.08, 8.08 Hz, 1H), 7.38-7.36 (m, 1H), 7.26-7.17 (m, 3H), 5.19 (s,2H), 4.78 (s, 4H), 3.72 (s, 2H), 3.37 (s, 4H), 1.72 (s, 4H). Compounds278-349, and 355 intentionally omitted.

In some embodiments, the invention includes a pharmaceutical compositioncomprising a compound described herein (e.g., a compound according toFormula I, II, or any of Compounds 100-128 or any of those in Tables 2or 3) or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable carrier.

In other embodiments, the invention features a method of inhibiting HDACactivity (e.g., HDAC2 activity) in a subject comprising the step ofadministering to a subject in need thereof an effective amount of acompound described herein (e.g., a compound according to Formula I, IIor any Compounds 100-128 or any of those in Tables 2 or 3) or apharmaceutically acceptable salt thereof, or a composition thereof.

In other embodiments, the invention features a method of treating acondition in a subject selected from a neurological disorder, memory orcognitive function disorder or impairment, extinction learning disorder,fungal disease or infection, inflammatory disease, hematologicaldisease, and neoplastic disease, comprising administering to a subjectin need thereof an effective amount of a compound described herein(e.g., a compound according to Formula I, II, or any of Compounds100-128 or any of those in Tables 2 or 3) or a pharmaceuticallyacceptable salt thereof, or a composition thereof.

In still other embodiments, the invention features a method of improvingmemory in a normal subject or treating, alleviating, or preventingmemory loss or impairment in a subject comprising administering to thesubject in need thereof an effective amount of a compound describedherein (e.g., a compound according to Formula I, II or any of Compounds100-128 or any of those in Tables 2 or 3) or a pharmaceuticallyacceptable salt thereof, or a composition thereof.

In certain embodiments, the condition is:

-   -   a. a cognitive function disorder or impairment associated with        Alzheimer's disease, Huntington's disease, seizure induced        memory loss, schizophrenia, Rubinstein Taybi syndrome, Rett        Syndrome, Fragile X, Lewy body dementia, vascular dementia,        frontotemporal dementia, ADHD, dyslexia, bipolar disorder and        social, cognitive and learning disorders associated with autism,        traumatic head injury, attention deficit disorder, anxiety        disorder, conditioned fear response, panic disorder, obsessive        compulsive disorder, posttraumatic stress disorder (PTSD),        phobia, social anxiety disorder, substance dependence recovery,        Age Associated Memory Impairment (AAMI), Age Related Cognitive        Decline (ARCD), ataxia, or Parkinson's disease; or    -   b. a hematological disease selected from acute myeloid leukemia,        acute promyelocytic leukemia, acute lymphoblastic leukemia,        chronic myelogenous leukemia, myelodysplastic syndromes, and        sickle cell anemia; or    -   c. a neoplastic disease; or    -   d. an extinction learning disorder selected from fear extinction        and post-traumatic stress disorder.

In further embodiments, the condition is Alzheimer's disease,Huntington's disease, frontotemporal dementia, Freidreich's ataxia,post-traumatic stress disorder (PTSD), Parkinson's disease, or substancedependence recovery.

In still other embodiments, the method is a combination therapy furthercomprising:

-   -   a. administering to the subject an effective amount of a        pharmaceutically active ingredient; and/or    -   b. exposing the subject to cognitive behavioral therapy (CBT),        psychotherapy, behavioral exposure treatments, virtual reality        exposure (VRE) and/or cognitive remediation therapy.

In other embodiments, the method is a combination therapy for treating,alleviating, and/or preventing post-traumatic stress disorder orAlzheimer's disease and the pharmaceutically active ingredientadministered is selected from Aricept®, memantine, galantamine andExcelon® (rivastigmine).

In some embodiments, the invention features a method of increasingsynaptic density or increasing synaptic plasticity or increasingdendritic density in a subject comprising administering to the subjectin need of such increase an effective amount of a compound describedherein (e.g., a compound according to Formula I, II or any of Compounds100-128 or any of those in Tables 2 or 3) or a pharmaceuticallyacceptable salt thereof, or a composition thereof.

In still other embodiments, a compound described herein (e.g., acompound according to Formula I, II or any of Compounds 100-128 or anyof those in Tables 2 or 3), a pharmaceutically acceptable salt thereof,or a compound or salt (e.g., a compound according to Formula I, II orany of Compounds 100-128 or any of those in Tables 2 or 3, or apharmaceutically acceptable salt thereof) in the pharmaceuticalcomposition selectively inhibits HDAC2.

In certain embodiments, a compound described herein (e.g., a compoundaccording to Formula I, II or any of Compounds 100-128 or any of thosein Tables 2 or 3), a pharmaceutically acceptable salt thereof, or acompound or salt (e.g., a compound according to Formula I, II or any ofCompounds 100-128 or any of those in Tables 2 or 3, or apharmaceutically acceptable salt thereof) in the pharmaceuticalcomposition compound has at least 2-, 5-, 10-, 15-, or 20-fold greaterinhibition of HDAC2 as compared to one or more other HDAC isoforms.

In further embodiments, the other HDAC isoform is HDAC1.

General Synthetic Methods and Intermediates:

The compounds of the present invention can be prepared by methods knownto one of ordinary skill in the art and/or by reference to the schemesshown below and the synthetic examples that follow. Exemplary syntheticroutes are set forth in the Schemes below, and in the Examples.

One of ordinary skill in the art will recognize that numerous variationsin reaction conditions including variations in solvent, reagents,catalysts, reaction temperatures and times are possible for each of thereactions described. Variation of order of synthetic steps andalternative synthetic routes are also possible.

The compounds of the present invention can be prepared by methods knownto one of ordinary skill in the art and/or by reference to the schemesshown below and the synthetic examples that follow.

4. Uses, Formulation and Administration

Exemplary Uses

Compounds of the invention are inhibitors of class I histonedeacetylases (HDAC) and in particular HDAC2, and are useful forpromoting cognitive function and enhancing learning and memoryformation. As a result, these compounds are useful in treating,alleviating, and/or preventing various conditions, including e.g.,neurological disorders, memory and cognitive functiondisorders/impairments, extinction learning disorders, fungal diseases,inflammatory diseases, hematological diseases, and neoplastic diseasesin humans and animals.

HDAC Inhibition

The compounds of the present invention are useful in a variety ofapplications for human and animal health. The compounds of the inventionare histone deacetylase (HDAC) inhibitors. A histone deacetylaseinhibitor as used herein is a compound that inhibits, reduces, orotherwise modulates the activity of histone deacetylase. HDACs catalyzethe removal of acetyl groups from lysine residues on proteins, includinghistones. HDAC inhibitors also show diverse biological functionsincluding effecting gene expression, cell differentiation, cell cycleprogression, growth arrest, and/or apoptosis. (J. Med. Chem. 2003,46:5097 and Curr. Med. Chem. 2003, 10:2343). In various embodiments, thecompounds of the invention reduce HDAC activity by at least about 50%,at least about 75%, or at least about 90% or more. In furtherembodiments, HDAC activity is reduced by at least about 95% or at leastabout 99% or more.

One aspect of the invention provides a method of inhibiting histonedeacetylase in a cell, comprising contacting a cell in which inhibitionof histone deacetylase is desired with an inhibition effective amount ofa compound of the invention or a composition thereof. Because compoundsof the invention inhibit histone deacetylase(s), they are usefulresearch tools for in vitro study of the role of histone deacetylase inbiological processes. Accordingly, in one aspect of the invention, thestep of contacting the cell is performed in vitro.

The term an “inhibiting effective amount” is meant to denote a dosagesufficient to cause inhibition of activity of one or more histonedeacetylase in a cell, which cell can be in a multicellular organism.The multicellular organism can be a plant, a fungus, or an animal,preferably a mammal, more preferably a human. The fungus may beinfecting a plant or a mammal, preferably a human, and could thereforebe located in and/or on the plant or mammal. If the histone deacetylaseis in a multicellular organism, the method according to this aspect ofthe invention comprises administering to the organism a compound orcomposition of the invention. Measurement of the effect of a compound ofthe invention on the enzymatic activity of a histone deacetylase isachieved using known methodologies. For example, Bradner, J. et al.Nature Chemical Biology, Vol. 6, March 2010, 238-243.

The potential of HDAC inhibitors is tremendous, but the development ofclinical compounds will likely require the design of isoform selectivecompounds to minimize side effect issues e.g., fatigue, anorexia,hematological and GI-toxicity. Isoform specific HDAC inhibitors provideadvantages by reducing toxicities associated with inhibition of otherHDACs. Specific HDAC inhibitors provide a higher therapeutic index,resulting in better tolerance by patients during chronic or long termtreatment. While several HDAC inhibitors are now in the clinic, most ofthese do not show significant selectivity for individual HDAC isoforms.

The compounds of the present invention inhibit HDAC2. In someembodiments, the compound reduces the activity of other, but fewer thanall histone deacetylases in the cell. In certain embodiments, thecompound reduces the activity of HDAC2 to a greater extent than otherhistone deacetylases.

In certain embodiments, the present invention relates to theaforementioned compound, wherein the compounds of the invention areselective HDAC2 inhibitors.

In one embodiment, a compound of the invention is selective for HDAC2and will have at least about 2-fold (e.g., at least about 5-fold,10-fold, 15-fold, or 20-fold) greater activity to inhibit HDAC2 ascompared to one or more other HDACs (e.g., one or more HDACs of class Ior II). In one embodiment, a compound of the invention will have atleast about 2-fold (e.g., at least about 5-fold, 10-fold, 15-fold, or20-fold) greater activity to inhibit HDAC2 as compared to HDAC3. In oneembodiment, a compound of the invention will have at least about 2-fold(e.g., at least about 5-fold, 10-fold, 15-fold, or 20-fold) greateractivity to inhibit HDAC2 as compared to HDAC1. In one embodiment, acompound of the invention will have at least about 2-fold (e.g., atleast about 5-fold, 10-fold, 15-fold, or 20-fold) greater activity toinhibit HDAC2 as compared to all other HDACs of a particular class ofHDACs (e.g., one or more HDACs of class I or II). In one embodiment, acompound of the invention will have at least about 2-fold (e.g., atleast about 5-fold, 10-fold, 15-fold, or 20-fold) greater activity toinhibit HDAC2 as compared to all other HDACs.

In another embodiment, a compound selectively inhibits HDAC2 with anIC₅₀ value greater than 0.0000001 μM and less than or equal to 0.1 μM, 1μM, 5 μM, or 30 μM.

The compounds described herein (e.g., a Compound of Formula I, II or anyof Compounds 100-128 or any of those in Tables 2 or 3) provide anadditional mechanism by which selectivity and an increased margin ofsafety may be obtained. In some embodiments, the compounds describedherein (e.g., a Compound of Formula I, II or any of Compounds 100-128 orany of those in Tables 2 or 3) partially inhibit the activity of HDAC2within specific cells. Without being limited by theory, this partialinhibition is hypothesized to be the result of differential potency onHDAC2 when it resides within a multiple protein complex in the cell. Themultiple protein complexes which contain HDAC2 vary between cells, withspecific complexes within specific cell types. Accordingly, thecompounds described herein (e.g., a Compound of Formula I, II or any ofCompounds 100-128 or any of those in Tables 2 or 3) compounds areproposed to incompletely inhibit the activity of HDAC2 in somecomplexes, sparing sufficient function of HDAC2 to provide an improvedmargin of safety while maintaining enough inhibition to result in thedesired effect.

Neurological Disorders

In one aspect, the invention provides methods and compositions fortreating, alleviating, and/or preventing neurological disorders.

Recent reports have detailed the importance of histone acetylation incentral nervous system (“CNS’) functions such as neuronaldifferentiation, memory formation, drug addiction, and depression(Citrome, Psychopharmacol. Bull. 2003, 37, Suppl. 2, 74-88; Johannessen,CNS Drug Rev. 2003, 9, 199-216; Tsankova et al., 2006, Nat. Neurosci. 9,519-525).

In one aspect, the invention provides methods and compositions fortreating, alleviating, and/or preventing neurological disorders. Theterm “neurological disorder” as used herein includes neurologicaldiseases, neurodegenerative diseases and neuropsychiatric disorders. Aneurological disorder is a condition having as a component a central orperipheral nervous system malfunction. Neurological disorders may causea disturbance in the structure or function of the nervous systemresulting from developmental abnormalities, disease, genetic defects,injury or toxin. These disorders may affect the central nervous system(e.g., the brain, brainstem and cerebellum), the peripheral nervoussystem (e.g., the cranial nerves, spinal nerves, and sympathetic andparasympathetic nervous systems) and/or the autonomic nervous system(e.g., the part of the nervous system that regulates involuntary actionand that is divided into the sympathetic and parasympathetic nervoussystems).

As used herein, the term “neurodegenerative disease” implies anydisorder that might be reversed, deterred, managed, treated, improved,or eliminated with agents that stimulate the generation of new neurons.Examples of neurodegenerative disorders include: (i) chronicneurodegenerative diseases such as familial and sporadic amyotrophiclateral sclerosis (FALS and ALS, respectively), familial and sporadicParkinson's disease, Huntington's disease, familial and sporadicAlzheimer's disease, multiple sclerosis, muscular dystrophy,olivopontocerebellar atrophy, multiple system atrophy, Wilson's disease,progressive supranuclear palsy, diffuse Lewy body disease,corticodentatonigral degeneration, progressive familial myoclonicepilepsy, strionigral degeneration, torsion dystonia, familial tremor,Down's Syndrome, Gilles de la Tourette syndrome, Hallervorden-Spatzdisease, diabetic peripheral neuropathy, dementia pugilistica, AIDSDementia, age related dementia, age associated memory impairment, andamyloidosis-related neurodegenerative diseases such as those caused bythe prion protein (PrP) which is associated with transmissiblespongiform encephalopathy (Creutzfeldt-Jakob disease,Gerstmann-Straussler-Scheinker syndrome, scrapie, and kuru), and thosecaused by excess cystatin C accumulation (hereditary cystatin Cangiopathy); and (ii) acute neurodegenerative disorders such astraumatic brain injury (e.g., surgery-related brain injury), cerebraledema, peripheral nerve damage, spinal cord injury, Leigh's disease,Guillain-Barre syndrome, lysosomal storage disorders such aslipofuscinosis, Alper's disease, restless leg syndrome, vertigo asresult of CNS degeneration; pathologies arising with chronic alcohol ordrug abuse including, for example, the degeneration of neurons in locuscoeruleus and cerebellum, drug-induced movement disorders; pathologiesarising with aging including degeneration of cerebellar neurons andcortical neurons leading to cognitive and motor impairments; andpathologies arising with chronic amphetamine abuse to includingdegeneration of basal ganglia neurons leading to motor impairments;pathological changes resulting from focal trauma such as stroke, focalischemia, vascular insufficiency, hypoxic-ischemic encephalopathy,hyperglycemia, hypoglycemia or direct trauma; pathologies arising as anegative side-effect of therapeutic drugs and treatments (e.g.,degeneration of cingulate and entorhinal cortex neurons in response toanticonvulsant doses of antagonists of the NMDA class of glutamatereceptor) and Wernicke-Korsakoff's related dementia. Neurodegenerativediseases affecting sensory neurons include Friedreich's ataxia,diabetes, peripheral neuropathy, and retinal neuronal degeneration.Other neurodegenerative diseases include nerve injury or traumaassociated with spinal cord injury. Neurodegenerative diseases of limbicand cortical systems include cerebral amyloidosis, Pick's atrophy, andRett syndrome. The foregoing examples are not meant to be comprehensivebut serve merely as an illustration of the term “neurodegenerativedisorder.”

In some instances the neurological disorder is a neuropsychiatricdisorder, which refers to conditions or disorders that relate to thefunctioning of the brain and the cognitive processes or behavior.Neuropsychiatric disorders may be further classified based on the typeof neurological disturbance affecting the mental faculties. The term“neuropsychiatric disorder,” considered here as a subset of“neurological disorders,” refers to a disorder which may be generallycharacterized by one or more breakdowns in the adaptation process. Suchdisorders are therefore expressed primarily in abnormalities of thought,feeling and/or behavior producing either distress or impairment offunction (i.e., impairment of mental function such with dementia orsenility). Currently, individuals may be evaluated for variousneuropsychiatric disorders using criteria set forth in the most recentversion of the American Psychiatric Association's Diagnostic andStatistical Manual of Mental Health (DSM-IV).

One group of neuropsychiatric disorders includes disorders of thinkingand cognition, such as schizophrenia and delirium. A second group ofneuropsychiatric disorders includes disorders of mood, such as affectivedisorders and anxiety. A third group of neuropsychiatric disordersincludes disorders of social behavior, such as character defects andpersonality disorders. A fourth group of neuropsychiatric disordersincludes disorders of learning, memory, and intelligence, such as mentalretardation and dementia. Accordingly, neuropsychiatric disordersencompass schizophrenia, delirium, attention deficit disorder (ADD),schizoaffective disorder, Alzheimer's disease, Rubinstein-Taybisyndrome, depression, mania, attention deficit disorders, drugaddiction, dementia, agitation, apathy, anxiety, psychoses, personalitydisorders, bipolar disorders, unipolar affective disorder,obsessive-compulsive disorders, eating disorders, post-traumatic stressdisorders, irritability, adolescent conduct disorder and disinhibition.

In one embodiment, the neurological disorder is Alzheimer's disease,Huntington's disease, seizure-induced memory loss, schizophrenia,Rubinstein Taybi syndrome, Rett Syndrome, Fragile X, Lewy body dementia,vascular dementia, ADHD, ADD, dyslexia, bipolar disorder and social,cognitive and learning disorders associated with autism, traumatic headinjury, or attention deficit disorder.

In another embodiment, the neurological disorder is an anxiety disorder,conditioned fear response, panic disorder, obsessive compulsivedisorder, post-traumatic stress disorder, phobia, social anxietydisorder, or substance dependence recovery.

In some embodiments neurological disorders are treated or prevented bydecreasing the amount of DNA damage within the neuronal cell. In someembodiments neurological disorders are treated or prevented byincreasing histone deacetylase activity within the neuronal cell. Insome embodiments neurological disorders are treated or prevented bydecreasing histone acetyl transferase activity within the neuronal cell.In some embodiments neurological disorders are treated or prevented byincreasing the activity of class I histone deacetylases.

Enhancing Cognitive Function

In one aspect, the invention provides methods and compositions forpromoting cognitive function and enhancing learning and memory formationin both normal subjects as well as those suffering from memory loss andcognitive function disorders/impairments. A normal subject, as usedherein, is a subject that has not been diagnosed with a disorderassociated with impaired cognitive function. “Cognitive function” refersto mental processes of a subject relating to information gatheringand/or processing; the understanding, reasoning, and/or application ofinformation and/or ideas; the abstraction or specification of ideasand/or information; acts of creativity, problem-solving, and possiblyintuition; and mental processes such as learning, perception, and/orawareness of ideas and/or information. The mental processes are distinctfrom those of beliefs, desires, and the like.

Memory Disorders/Impairment

Transcription is thought to be a key step for long-term memory processes(Alberini, 2009, Physiol. Rev. 89, 121-145). Transcription is promotedby specific chromatin modifications, such as histone acetylation, whichmodulate histone-DNA interactions (Kouzarides, 2007, Cell, 128:693-705).Modifying enzymes, such as histone acetyltransferases (HATs) and histonedeacetylases (HDACs), regulate the state of acetylation on histonetails. In general, histone acetylation promotes gene expression, whereashistone deacetylation leads to gene silencing. Numerous studies haveshown that a potent HAT, cAMP response element-binding protein(CREB)-binding protein (CBP), is necessary for long-lasting forms ofsynaptic plasticity and long term memory (for review, see Barrett, 2008,Learn Mem 15:460-467).

A “memory” as used herein refers to the ability to recover informationabout past events or knowledge. Memories include short-term memory (alsoreferred to as working or recent memory) and long-term memory.Short-term memories involve recent events, while long-term memoriesrelate to the recall of events of the more distant past. Methods ofassessing the ability to recall a memory are known to those of skill inthe art and may involve routine cognitive tests. Enhancing or retrievingmemories is distinct from learning. However, in some instances in theart learning is referred to as memory. Learning, unlike memoryenhancement, refers to the ability to create new memories that had notpreviously existed. Thus in order to test the ability of a compound toeffect the ability of a subject to learn rather than recall oldmemories, the compound would be administered prior to or at the sametime as the memory is created. In order to test the ability of acompound to affect recall of a previously created memory the compound isadministered after the memory is created and preferably after the memoryis lost.

As used herein “age related memory loss” refers to any of a continuum ofconditions characterized by a deterioration of neurological functioningthat does not rise to the level of a dementia, as further defined hereinand/or as defined by the Diagnostic and Statistical Manual of MentalDisorders: 4th Edition of the American Psychiatric Association (DSM-IV,1994). Age related memory loss is characterized by objective loss ofmemory in an older subject compared to his or her younger years, butcognitive test performance that is within normal limits for thesubject's age. Age related memory loss subjects score within a normalrange on standardized diagnostic tests for dementias, as set forth bythe DSM-IV. Moreover, the DSM-IV provides separate diagnostic criteriafor a condition termed Age-Related Cognitive Decline. In the context ofthe present invention, as well as the terms “Age-Associated MemoryImpairment” and “Age-Consistent Memory Decline” are understood to besynonymous with the age related memory loss. Age-related memory loss mayinclude decreased brain weight, gyral atrophy, ventricular dilation, andselective loss of neurons within different brain regions. For purposesof some embodiments of the present invention, more progressive forms ofmemory loss are also included under the definition of age-related memorydisorder. Thus persons having greater than age-normal memory loss andcognitive impairment, yet scoring below the diagnostic threshold forfrank dementia, may be referred to as having a mild neurocognitivedisorder, mild cognitive impairment, late-life forgetfulness, benignsenescent forgetfulness, incipient dementia, provisional dementia, andthe like. Such subjects may be slightly more susceptible to developingfrank dementia in later life (See also US patent application 2006/008517(Vasogen Ireland limited) which is incorporated by reference). Symptomsassociated with age-related memory loss include but are not limited toalterations in biochemical markers associated with the aging brain, suchas IL-1 beta, IFN-gamma, p-JNK, p-ERK, reduction in synaptic activity orfunction, such as synaptic plasticity, evidenced by reduction in longterm potentiation, diminution of memory and learning.

As used herein “injury related memory loss” refers to a loss of memorywherein there is damage to the brain, and there may have also beenneurological damage. Sources of brain injury include traumatic braininjury such as concussive injuries or penetrating head wounds, braintumors, alcoholism, Alzheimer's disease, stroke, heart attack and otherconditions that deprive the brain of oxygen, meningitis, AIDS, viralencephalitis, and hydrocephalus.

Methods for enhancing memories can include reestablishing access tomemories as well as recapturing memories. The term re-establishingaccess as used herein refers to increasing retrieval of a memory.Although Applicants are not bound by a mechanism of action, it isbelieved that the compounds of the invention are effective in increasingretrieval of memories by re-establishing a synaptic network. The processof re-establishing a synaptic network may include an increase in thenumber of active brain synapses and or a reversal of neuronal loss.

Neurogenesis, or the birth of new neuronal cells, was thought to occuronly in developing organisms. However, recent research has demonstratedthat neurogenesis does indeed continue into and throughout adult life.On going neurogenesis is thought to be an important mechanism underlyingneuronal plasticity, enabling organisms to adapt to environmentalchanges and influencing learning and memory throughout life. In oneaspect, the invention includes a method of increasing synaptic densityin a subject comprising administering to the subject in need of suchincrease a compound of the invention or a pharmaceutically acceptablesalt, hydrate, solvate, or prodrug thereof. In one aspect, the inventionincludes a method of increasing synaptic plasticity in a subjectcomprising administering to the subject in need of such increase acompound of the invention or a pharmaceutically acceptable salt,hydrate, solvate, or prodrug thereof. In one aspect, the inventionincludes a method of increasing dendritic density in neurons in asubject comprising administering to the subject in need of such increasea compound of the invention or a pharmaceutically acceptable salt,hydrate, solvate, or prodrug thereof.

The invention provides methods for enhancing memory in a subject havinga memory disorder. Examples of types of memory disorders includeAlzheimer's disease, absent-minded professor, absent-mindedness,amnesia, anterograde amnesia, blackout (alcohol-related amnesia),bromism, childhood amnesia, false memory syndrome, fugue state,hyperthymesia, Korsakoff's syndrome, lacunar amnesia, memory distrustsyndrome, memory loss, post-traumatic amnesia, prosopamnesia,psychogenic amnesia, repressed memory, retrograde amnesia, Ribot's Law,selective memory loss, source amnesia, source-monitoring error, theseven sins of memory, tip of the tongue, transient epileptic amnesia,transient global amnesia, and twilight sleep.

In one embodiment, Alzheimer's disease is the memory disorder. Suchmethods optionally involve administering the inhibitor and monitoringthe subject to identify recapture of a memory that was previously lost.Subjects may be monitored by routine tests known in the art.

In other embodiments the alzheimer's subject is one that has late stageAlzheimer's disease. Many of the drugs suggested for treatingAlzheimer's disease are designed to treat the early stages of thedisease by preventing plaque buildup. The compounds of the invention areuseful for treating both early stages and late stages of dementiabecause they actually improve memory and cognition rather thanpreventing only plaque accumulation.

Cognitive Function Disorders/Impairment

The invention relates to methods of treating, alleviating, and/orpreventing cognitive function disorders/impairments.

Impaired cognitive function refers to cognitive function that is not asrobust as that observed in an age-matched normal subject and includesstates in which cognitive function is reduced. In some cases, cognitivefunction is reduced by about 5%, about 10%, about 30%, or more, comparedto cognitive function measured in an age-matched normal subject.Cognitive function may be promoted to any detectable degree, but inhumans preferably is promoted sufficiently to allow an impaired subjectto carry out daily activities of normal life.

In some embodiments, the cognitive function disorders or impairments areassociated with, but not limited to, Alzheimer's disease, Huntington'sdisease, seizure induced memory loss, schizophrenia, Rubinstein Taybisyndrome, Rett Syndrome, Fragile X, Lewy body dementia, Vasculardementia, bipolar disorder and social, cognitive and learning disordersassociated with autism, attention deficit hyperactivity disorder (ADHD),dyslexia, learning disorders, traumatic head injury, stroke inducedcognitive and motor impairment, traumatic brain injury,neurodegeneration and neuronal loss mediated cognitive impairment, andattention deficit disorder.

In some embodiments, the cognitive function disorders or impairments areassociated with, but not limited to, anxiety disorders, conditioned fearresponse, panic disorders, obsessive compulsive disorders,post-traumatic stress disorder, phobias, social anxiety disorders,substance dependence recovery or Age Associated Memory Impairment(AAMI), and Age Related Cognitive Decline (ARCD).

In some embodiments, the invention relates to methods of treating,alleviating, and/or preventing vascular dementia. Vascular dementia,also referred to as “multi-infarct dementia”, refers to a group ofsyndromes caused by different mechanisms all resulting in vascularlesions in the brain. The main subtypes of vascular dementia are, forexample vascular mild cognitive impairment, multi-infarct dementia,vascular dementia due to a strategic single infarct (affecting thethalamus, the anterior cerebral artery, the parietal lobes or thecingulate gyms), vascular dementia due to hemorrhagic lesions, smallvessel disease (including, e.g. vascular dementia due to lacunar lesionsand Binswanger disease), and mixed Alzheimer's Disease with vasculardementia.

In some embodiments, the invention relates to treating, alleviating,and/or preventing Huntington's disease. Huntington's disease is aneurological disease which results in cognitive decline associated withinexorable progression to death. Cognitive symptoms associated withHuntington's disease include loss of intellectual speed, attention, andshort term memory and/or behavioral symptoms.

Cognitive function may be assessed, and thus optionally defined, via oneor more tests or assays for cognitive function. Non-limiting examples ofa test or assay for cognitive function include CANTAB (see for exampleFray et al. “CANTAB battery: proposed utility in neurotoxicology.”Neurotoxicol Teratol 1996; 18(4):499-504), Stroop Test, Trail Making,Wechsler Digit Span, or the CogState computerized cognitive test (seealso Dehaene et al. “Reward-dependent learning in neuronal networks forplanning and decision making.” Brain Res. 2000; 126:21729; Iverson etal. “Interpreting change on the WAIS-III/WMS-III in clinical samples.”Arch Clin Neuropsychol. 2001; 16(2):183-91; and Weaver et al. “Mildmemory impairment in healthy older adults is distinct from normalaging.” Cogn. 2006; 60(2):146-55). The methods of the invention may beused to promote cognitive function in a normal subject or to treat,alleviate and/or prevent a subject from having a cognitive dysfunction.A normal subject, as used herein, is a subject that has not beendiagnosed with a disorder associated with impaired cognitive function.

Extinction Learning Disorders

In one aspect, the invention relates to methods of treating,alleviating, and/or preventing extinction learning disorders e.g., afear extinction deficit.

It has been demonstrated that administration of the HDAC inhibitorssodium butyrate or trichostatin A facilitates fear extinction in miceand this enhancement mirrors that caused by commonly used behavioralmanipulation and is consistent with other studies demonstrating a rolefor the hippocampus in the extinction of contextual fear (Lattal, etal., 2007, Behav. Neurosci. 121, 5, 1125-1131).

Compounds of the invention can be used to facilitate the psychologicalprocess of extinction learning and thus are useful for treating,alleviating, and/or preventing neuropsychiatric disorders and otherrelated disorders. Unlike traditional anti-anxiety drugs that areadministered on a chronic basis and address physiological symptoms ofanxiety, the compounds of the invention can be used on a chronic oracute basis in conjunction with a second therapy e.g., psychotherapy.

In one aspect, the present invention is directed to methods fortreating, alleviating, and/or preventing a subject from having aneuropsychiatric disorder. The methods comprise subjecting the subjectto one or more sessions of a combination therapy protocol, where thecombination therapy protocol comprises an acute administration of atherapeutically effective amount of a compound of the invention thatenhances learning or conditioning in combination with a session ofpsychotherapy. By “acute administration” is intended a single exposureof the subject to the therapeutically effective amount of the compoundthat enhances learning or conditioning. In one aspect, the exposure tothe compound occurs within about 24 hours prior to initiating thesession of psychotherapy, preferably within about 12 hours, and morepreferably within about 6 hours prior to initiating the session ofpsychotherapy. A full course of treatment for the neuropsychiatricdisorder entails at least one session of this combination therapyprotocol.

For purposes of the present invention, a subject may have a singledisorder, or may have a constellation of disorders that are to betreated, alleviated, and/or prevented by the methods described herein.

The neuropsychiatric disorders contemplated in the present inventioninclude, but are not limited to, fear and anxiety disorders, addictivedisorders including substance-abuse disorders, and mood disorders.Within the fear and anxiety disorder category, the invention encompassesthe treatment or prevention of panic disorder, specific phobia,post-traumatic stress disorder (PTSD), obsessive-compulsive disorder,and movement disorders such as Tourette's syndrome. The disorderscontemplated herein are defined in, for example, the DSM-IV (Diagnosticand Statistical Manual of Mental Disorders (4th ed., AmericanPsychiatric Association, Washington D.C., 1994)), which is hereinincorporated by reference.

Anxiety-related disorders relate to those disorders characterized byfear, anxiety, addiction, and the like. Patients with anxiety-relateddisorders can have a single such disorder, or can have a constellationof disorders. The anxiety-related disorders contemplated in the presentinvention include, but are not limited to, anxiety disorders, addictivedisorders including substance-abuse disorders, mood disorders (e.g.,depression and/or bipolar disorder), movement disorders such asTourette's syndrome, psychogenic erectile dysfunction (impotenceresulting from a man's inability to obtain or maintain an erection ofhis penis), insomnia (e.g. chronic insomnia), and eating disorders (e.g.anorexia).

Anxiety disorders include, but are not limited to, panic disorder,agoraphobia, social phobia, specific phobia, PTSD, obsessive-compulsivedisorder, and generalized anxiety disorder. The disorders contemplatedherein are defined in, for example, the DSM-IV (Diagnostic andStatistical Manual of Mental Disorders (4th ed., American PsychiatricAssociation, Washington D.C., 1994)).

Movement disorders are neurological conditions that affect the speed,fluency, quality, and ease of movement. Representative movementdisorders include but are not limited to ataxia, chorea, myoclonus,dystonia, Parkinson's disease, restless leg syndrome, tics, andTourette's syndrome. Movement disorders typically occur as a result ofdamage or disease in the basal ganglia region of the brain. Movementdisorders can result from age-related changes, medications, geneticdisorders, metabolic disorders, disease, stroke, or injury. Recovery ofmovement after stroke or injury may be facilitated when treatedaccording to the methods of the invention.

Addictive disorders are disorders characterized by addiction to anactivity or substance, and include, for example, alcohol addiction, drugaddiction, and gambling addiction.

Depression refers to the clinical condition known as major depressivedisorder, and is characterized by a state of intense sadness,melancholia, or despair that has advanced to the point of beingdisruptive to an individual's social functioning and/or activities ofdaily living. Depression is alleviated if either (or both) the severityor frequency of a symptom of the depression is reduced. However, asubject can be treated for depression in accordance with the methods ofthe invention irrespective of whether the treatment actually wassuccessful in alleviating the depression.

Insomnia is defined herein as the inability to fall asleep or to stayasleep for a sufficient amount of time during regular sleeping hours. Itincludes acute insomnia, which occurs in either a transient or shortterm form, and chronic insomnia. It also includes initial insomnia,defined as difficulty in falling asleep; middle insomnia, defined asawakening in the middle of the night followed by eventually falling backto sleep, but with difficulty; and terminal insomnia, defined asawakening before one's usual waking time and being unable to return tosleep.

As defined by the National Institute of Mental Health, Autism SpectrumDisorders (ASD), also widely known as Pervasive Developmental Disorders(PDDs), cause severe and pervasive impairment in thinking, feeling,language, and the ability to relate to others. These disorders areusually first diagnosed in early childhood and range from a severe form,called autistic disorder, through pervasive development disorder nototherwise specified (PDD-NOS), to a much milder form, Asperger syndrome.They also include two rare disorders, Rett syndrome and childhooddisintegrative disorder.

Attention-Deficit Hyperactivity Disorder (ADHD) is one of the mostcommon mental disorders that develop in children. Children with ADHDtypically have impaired functioning in multiple settings, includinghome, school, and in relationships with peers. Symptoms of ADHD includeimpulsiveness, hyperactivity, and inattention.

Typical treatments encompassed by the present invention includecombination therapies. For instance, the combination therapy may be apharmacotherapy (i.e., a compound of the invention) and a behavioraltherapy. Behavioral therapy comprises, but is not limited to,electroconvulsive seizure therapy, exercise, group therapy, talktherapy, or conditioning. In another embodiment, the behavioral therapyis cognitive-behavioral therapy. Examples of behavioral therapy that maybe used in the ongoing methods are described, for example, inCognitive-Behavioral Therapies by K. Dobson, ed., Guilford Publications,Inc., 2002; The new Handbook of Cognitive Therapy: Basics and Beyond byJudith S. S. Beck, Guilford Publications, Inc. 1995 herein incorporatedby reference in their entireties. Any pharmaceutical active ingredientthat is recognized by the skilled artisan as being a pharmacologic agentthat enhances learning or conditioning can be used in the methods of theinvention. For example, one such class of pharmaceutical activeingredients contemplated herein comprises compounds that increase thelevel of norepinephrine in the brain. Such compounds include thoseacting as norepinephrine reuptake inhibitors, for example tomoxetine,reboxetine, duloxetine, venlafaxine, and milnacipran, and thosecompounds that cause release of norepinephrine, for example amphetamine,dextroamphetamine, pemoline, and methylphenidate. Another class of suchpharmaceutical active ingredients is those compounds that increase thelevel of acetylcholine in the brain, including, for example, compoundsthat block its breakdown. Examples of such compounds include, but arenot limited to, donepezil HCl or Aricept™ and tacrine, which inhibitcholinesterase activity.

Methods of the invention also encompass the use in combination with acompound of the invention of any type of psychotherapy that is suitablefor the particular psychiatric disorder for which the subject isundergoing treatment. Suitable methods of psychotherapy include exposurebased psychotherapy, cognitive psychotherapy, and psychodynamicallyoriented psychotherapy. Methods of the invention also encompass exposingthe subject to cognitive behavioral therapy (CBT), behavioral exposuretreatments, virtual reality exposure (VRE) or cognitive remediationtherapy.

Methods of the invention also encompass extinction training. The goal ofextinction training is to pair a stimulus that previously provoked adeleterious, unwanted response with a new learning that will not lead toa negative outcome, thereby generating in a subject a new, moreappropriate response to the stimulus to compete with and ideally replacethe previous undesirable response. Extinction training frequentlyexposes a subject to a stimulus or situation in the absence of anaversive consequence, e.g., a subject that has deleterious, high anxietyresponses to a given stimulus or situation is exposed to that stimulusor situation in the absence of an aversive consequence. A typical goalof extinction training is to produce new learning in the subject thatresults from the pairing of the original stimulus or situation with anon-deleterious outcome, thereby generating, in subsequent exposures tothe stimulus, a more appropriate response in place of the unwantedresponse. An extinction learning event refers to a completedstimulus/response extinction training cycle.

One form of extinction training entails psychotherapy. For example, themethods of the invention contemplate treating, alleviating, and/orpreventing anxiety disorders by: (i) administering psychotherapy totreat, alleviate, and/or prevent an anxiety-related disorder in asuitable human subject, and (ii) administering a therapeuticallyeffective dose a compound of the invention to said subject on anachronic, post-training, pre-sleep basis. Suitable methods ofpsychotherapy include but are not limited to exposure-basedpsychotherapy, cognitive psychotherapy, and psychodynamically orientedpsychotherapy.

One method of psychotherapy that is specifically contemplated is the useof virtual reality (VR) exposure therapy to treat, alleviate, and/orprevent an anxiety disorder using the methods of the invention.

Another method of psychotherapy that is particularly beneficial whenutilized in combination with a compound or composition of the presentinvention is cognitive behavioral therapy (“CBT”). CBT is a form ofpsychotherapy that combines cognitive therapy and behavior therapy, andemphasizes the critical role of thinking in causing people to act andfeel as they do. Therefore, if an individual is experiencing unwantedfeelings and behaviors, CBT teaches that it is important to identify thethinking that is causing the undesirable feelings and/or behaviors andto learn how to replace this deleterious thinking with thoughts thatlead to more desirable reactions. CBT is widely used to help people whoare experiencing a range of mental health difficulties, some of which donot conveniently fit definitions of a particular medical affliction. CBThas been used to treat anxiety disorders, mood disorders, addictivedisorders, eating disorders, insomnia, chronic pain, schizophrenia,fibromyalgia, ADHD, and autism spectrum disorders, among others.Post-extinction training pre-sleep administration of a compound of theinvention, subsequent to CBT treatment, can be used to augment theeffectiveness of the CBT treatment for these medical conditions.

In one embodiment, subjects suffering from social anxiety disorderundergo weekly cognitive behavioral therapy sessions to treat theaffliction. After each therapy session, subjects are administered atherapeutically effective formulation of compounds of the invention on apost-extinction training pre-sleep basis. Relative to subjects treatedonly via cognitive behavioral therapy, or to subjects treated viacognitive behavioral therapy and a placebo, anxiety associated withsocial anxiety disorder is expected to be reduced to a greater extent insubjects treated with a combination of cognitive behavioral therapy andachronic administration of a compound of the invention on apost-extinction training pre-sleep basis.

In another embodiment of the invention, a compound of the invention isadministered after extinction training only if the extinction trainingyields positive results on that day. For example, a subject undergoingcognitive behavioral therapy for PTSD is administered a compound of theinvention on a post-extinction training only if the cognitive behavioraltherapy was deemed to be successful, as determined by the subject and/ortherapist. In one aspect, the compound is administered on apost-extinction, pre-sleep basis. In another aspect, a subjectundergoing cognitive behavioral therapy for PTSD is administered acompound of the invention on a pre-extinction training. In one aspect,the compound is administered on a pre-extinction, pre-sleep basis. Thismethod may also be useful when applied to treatment of autism spectrumdisorders or attention-deficit hyperactivity disorder.

In some embodiments, the invention relates to treating a condition wherethe treating comprises re-writing memories. Memories of an event oftenhave an associated emotional component. For example, memories of atraumatic event can cause feelings of grief, guilt, or loss, as well asnegative emotional responses such as anger, rage or aggression.Conversely, memories of a positive events can cause joy and increasefeelings of self-confidence and self-worth. During the period of timewhen a memory is recalled it can modified to alter the associations andreduce or alter the emotional reactions to it. In some embodiments, HDACinhibitors in combination with cognitive behavioral therapy or virtualreality therapy may allow the emotional associations with a memory to bere-written producing a longer term or greater therapeutic benefit.

In another embodiment of the invention, subjects afflicted with anxietydisorders such as PTSD receive extinction training using Eye MovementDesensitization and Reprocessing (EMDR), and subsequently areadministered a therapeutically effective dose of a compound of theinvention on a post-extinction training pre-sleep basis.

Another form of extinction training is provided by biofeedback, which isparticularly useful in enabling subjects to learn to controlphysiological processes that normally occur involuntarily, such as bloodpressure, heart rate, muscle tension, and skin temperature. As usedherein, “biofeedback” refers to a technique in which subjects aretrained to improve their health by using signals from their own bodiesto control their own physiological responses.

In one embodiment of the invention, a subject suffering from chronicpain undergoes biofeedback sessions to help alleviate the pain. Upon theconclusion of each session wherein the subject has made progress inlearning/developing responses that reduce the chronic pain, the subjectis administered a compound of the invention on a post-extinctiontraining pre-sleep basis in order to consolidate the desired learning.

In another embodiment, a subject suffering from phantom limb syndromeundergoes thermal biofeedback sessions to reduce and hopefully eliminatethe symptoms. After each session, the subject is administered atherapeutically effective formulation of a compound of the invention ona post-extinction training pre-sleep basis.

In another embodiment, extinction training can be provided by physicaltherapy, or virtual reality physical therapy such as virtual realitygait therapy. For example, a stroke victim re-learning how to walk canundergo virtual reality gait therapy, and then be administered acompound of the invention on an achronic, post-extinction trainingpre-sleep basis.

Another form of extinction training can be provided by pharmacotherapy.See, e.g., Davis et al., NeuroRx: The Journal of the American Societyfor Experimental NeuroTherapeutics, 93:82-96, 2006. For example,manipulation of the endogenous cannabinoid (eCB) is of interest bothbecause of the potential for identifying new therapeutics to treat,e.g., mental illness and disorders, but also due to the dense expressionof the CB1 receptor in regions associated with, e.g., anxiety andemotional learning. For example, studies have shown that both geneticCB1 knockout mice and mice subjected to pharmacological blockate of theCB1 receptor exhibited a similar effect in extinction (Davis, page 87).Studies using the CB1 antagonist rimonabant in rats showed that systemicadministration of this drug led to significant and dose-dependentdecreases in extinction. Together with other studies relating to theadministration of CB1 agonist WIN 55,212-2 and of an inhibitor of CB1reuptake and breakdown, the CB1 receptor can be important in extinctionlearning and modulation of the endocannabinoid system can be used todecrease or increase extinction.

Extinction training does not always require intervention of a trainedspecialist. Individuals can carry out extinction training on themselves.

Fungal Diseases or Infections

In some aspects, the invention relates to a method for treating,alleviating, and/or preventing a fungal disease or infection comprisingadministering to a subject a compound of the invention. The inventionprovides a method for treating, alleviating, and/or preventinghospital-acquired fungal infections that attack immunocompromisedpatients including those with HIV and cancer. In one embodiment, theinvention provides a method for treating, alleviating, and/or preventinga fungal disease in a subject not suffering from cancer.

Inflammatory Disease

In some aspects, the invention relates to a method for treating,alleviating, and/or preventing an inflammatory disease, including butnot limited to stroke, rheumatoid arthritis, lupus erythematosus,ulcerative colitis and traumatic brain injuries (Leoni et al., PNAS,99(5); 2995-3000 (2002); Suuronen et al. J. Neurochem. 87; 407-416(2003) and Drug Discovery Today, 10: 197-204 (2005).

Neoplastic Diseases

In some aspects, the invention relates to methods of selectivelyinducing terminal differentiation, and arresting cell growth and/orapoptosis of neoplastic cells, thereby inhibiting proliferation of suchcells. The compounds of the present invention are useful in treating,alleviating, and/or preventing cancer in a subject.

The term “cancer” refers to any cancer caused by the proliferation ofneoplastic cells, such as solid tumors, neoplasms, carcinomas, sarcomas,leukemias, lymphomas and the like. In particular, cancers that may betreated, alleviated and/or prevented by the compounds of the inventioninclude, but are not limited to: cardiac cancer, lung cancer,gastrointestinal cancer, genitourinary tract cancer, liver cancer,nervous system cancer, gynecological cancer, hematologic cancer, skincancer, and adrenal gland cancer.

In some embodiments, the compounds of the invention relate to treating,alleviating, or preventing cardiac cancers selected from sarcoma(angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma,rhabdomyoma, fibroma, lipoma and teratoma.

In some embodiments, the compounds of the invention relate to treating,alleviating, or preventing lung cancer selected from bronchogeniccarcinoma (squamous cell, undifferentiated small cell, undifferentiatedlarge cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, and mesothelioma.

In some embodiments, the compounds of the invention relate to treating,alleviating or preventing gastrointestinal cancer selected fromesophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoidtumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), and large bowel (adenocarcinoma, tubular adenoma, villousadenoma, hamartoma, leiomyoma).

In some embodiments, the compounds of the invention relate to treating,alleviating, and/or preventing genitourinary tract cancer selected fromkidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma,leukemia), bladder and urethra (squamous cell carcinoma, transitionalcell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), andtestis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma).

In some embodiments, the compounds of the invention relate to treating,alleviating, and/or preventing liver cancer selected from hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, and hemangioma.

In some embodiments, the compounds of the invention relate to treating,alleviating, and/or preventing bone cancer selected from osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochondroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors.

In some embodiments, the compounds of the invention relate to treating,alleviating, and/or preventing nervous system cancer selected from skull(osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastomamultiform, oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma).

In some embodiments, the compounds of the invention relate to treating,alleviating, and/or preventing gynecological cancer selected from uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

In some embodiments, the compounds of the invention relate to treating,alleviating, and/or preventing skin cancer selected from malignantmelanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi'ssarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma,keloids, and psoriasis.

In some embodiments, the compounds of the invention relate to methods oftreating, alleviating, and/or preventing adrenal gland cancer selectedfrom neuroblastoma.

In some embodiments, the instant compounds are useful in the treatment,alleviation, and/or preventing of cancers that include, but are notlimited to: leukemias including acute leukemias and chronic leukemiassuch as acute lymphocytic leukemia (ALL), Acute myeloid leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML)and Hairy Cell Leukemia; lymphomas such as cutaneous T-cell lymphomas(CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associatedwith human T-cell lymphotropic virus (HTLV) such as adult T-cellleukemia/lymphoma (ATLL), Hodgkin's disease and non-Hodgkin's lymphomas,large-cell lymphomas, diffuse large B-cell lymphoma (DLBCL); Burkitt'slymphoma; mesothelioma, primary central nervous system (CNS) lymphoma;multiple myeloma; childhood solid tumors such as brain tumors,neuroblastoma, retinoblastoma, Wilm's tumor, bone tumors, andsoft-tissue sarcomas, common solid tumors of adults such as head andneck cancers (e.g., oral, laryngeal and esophageal), genito urinarycancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular,rectal and colon), lung cancer, breast cancer, pancreatic cancer,melanoma and other skin cancers, stomach cancer, brain tumors, livercancer and thyroid cancer.

Hematologic Diseases

In some aspects, the invention relates to methods of treating,alleviating, or preventing hematological diseases. Hematologic diseasesinclude abnormal growth of blood cells which can lead to dysplasticchanges in blood cells and hematologic malignancies such as variousleukemias. Examples of hematologic diseases include but are not limitedto acute myeloid leukemia, acute promyelocytic leukemia, acutelymphoblastic leukemia, chronic myelogenous leukemia, themyelodysplastic syndromes, and sickle cell anemia.

Acute myeloid leukemia (AML) is the most common type of acute leukemiathat occurs in adults. Several inherited genetic disorders andimmunodeficiency states are associated with an increased risk of AML.These include disorders with defects in DNA stability, leading to randomchromosomal breakage, such as Bloom's syndrome, Fanconi's anemia,Li-Fraumeni kindreds, ataxia-telangiectasia, and X-linkedagammaglobulinemia.

Acute promyelocytic leukemia (APML) represents a distinct subgroup ofAML. This subtype is characterized by promyelocytic blasts containingthe 15;17 chromosomal translocation. This translocation leads to thegeneration of the fusion transcript comprised of the retinoic acidreceptor and a sequence PML.

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease withdistinct clinical features displayed by various subtypes. Reoccurringcytogenetic abnormalities have been demonstrated in ALL. The most commoncytogenetic abnormality is the 9;22 translocation. The resultantPhiladelphia chromosome represents poor prognosis of the patient.

Chronic myelogenous leukemia (CML) is a clonal myeloproliferativedisorder of a pluripotent stem cell. CML is characterized by a specificchromosomal abnormality involving the translocation of chromosomes 9 and22, creating the Philadelphia chromosome. Ionizing radiation isassociated with the development of CML.

The myelodysplastic syndromes (MDS) are heterogeneous clonalhematopoietic stem cell disorders grouped together because of thepresence of dysplastic changes in one or more of the hematopoieticlineages including dysplastic changes in the myeloid, erythroid, andmegakaryocytic series. These changes result in cytopenias in one or moreof the three lineages. Patients afflicted with MDS typically developcomplications related to anemia, neutropenia (infections), orthrombocytopenia (bleeding). Generally, from about 10% to about 70% ofpatients with MDS develop acute leukemia.

Sickle cell disease is attributable to homozygous inheritance of asingle amino acid substitution in the β-globin gene that leads topolymerization of deoxygenated hemoglobin, deformation of red bloodcells, microvascular occlusion, hemolysis, and consequent diseasemanifestations, including pain, strokes, and pulmonary complications(Bunn H F, 1997, J. Med. 337:762-769). Abundant biochemical,epidemiological, and clinical evidence have shown that a high level of γglobin, the fetal form of 3 globin, inhibits the aberrant polymerizationof sickle hemoglobin and ameliorates the disease phenotype. The onlyFood and Drug Administration (FDA)-approved drug for sickle celldisease, hydroxyurea, causes significant induction of fetal hemoglobin,decreased disease severity, and benefits overall mortality (Letvin etal., 1984, N Engl J Med 310:869-873; Platt O S, et al., 1984, J ClinInvest 74:652-656; Charache S, et al., 1995, N Engl J. Med 332:317-1322; Steinberg M H, et al., 2003, JAMA 289:1645-1651).Nevertheless, hydroxyurea has bone marrow-suppressive effects and isineffective in a significant portion of patients (Charache S, et al.;Steinberg M H, et al., 2003; Steinberg M H, 1999, N Engl J. Med340:1021-1030). A drug that induces fetal hemoglobin more substantiallywith less myelosuppression would be expected to have greater therapeuticutility in sickle cell disease.

Transcriptional regulation of the human globin gene locus has beeninvestigated intensively. Gamma-globin gene expression is influenced bytranscription factors (GATA-1, EKLF, NF-E4p22, Ikaros) and chromatinmodifying enzymes [SWI/SNF complex, HATs, and histone deacetylase(HDACs)] as part of multiprotein complexes, and a unique, dynamicchromatin structure termed the β-globin active chromatin hub (βACH)(8-11). Polymorphisms in BCL11A, a transcriptional repressor, alterbaseline fetal hemoglobin levels, and a multiprotein complex containingBCL11a binds to the β-globin locus, resulting in repression of γ-globinexpression (Menzel S, et al., 2007, Nat Genet 39:1197-1199; Lettre G, etal., 2008, Proc Natl Acad Sci USA 105:11869-11874;

Sankaran V G, et al., 2008, Science 322:1839-1842; Uda M, et al., 2008,Proc NATL Acad Sci USA 105:1620-1625; Sankaran V G, et al., 2009, Nature460:1093-1097). Despite this granularity, discrete targets amenable toligand discovery efforts have not been identified and functionallyvalidated.

The induction of fetal hemoglobin is a validated strategy to improvesymptoms and complications of sickle cell disease. The development oftargeted therapies has been limited by the absence of discrete druggabletargets. Bradner et al., 2010, PNAS, 107:28, 12617-12622 has developed aunique bead-based strategy for the identification of inducers of fetalhemoglobin transcripts in primary human erythroid cells, which includesa small-molecule screen of bioactive compounds that have been identifiedto have remarkable class-associated activity among histone deacetylase(HDAC) inhibitors. Using a chemical genetic strategy combining focusedlibraries of biased chemical probes and reverse genetics by RNAinterference, Bradner et al. identified HDAC1 and HDAC2 as moleculartargets mediating fetal hemoglobin induction. Isoform-selectiveinhibitors of HDAC1 and HDAC2 are targets for the treatment of sicklecell disease.

Pharmaceutical Compositions

Accordingly, in another aspect of the present invention, pharmaceuticalcompositions are provided, wherein these compositions comprise any ofthe compounds as described herein, and optionally comprise apharmaceutically acceptable carrier, adjuvant or vehicle. In certainembodiments, these compositions optionally further comprise one or moreadditional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable prodrugs, salts,esters, salts of such esters, or any other adduct or derivative whichupon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of an HDAC isoform as described herein.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersible products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In yet another aspect, a method for treating a proliferative,inflammatory, or cardiovascular disorder is provided comprisingadministering an effective amount of a compound, or a pharmaceuticalcomposition to a subject in need thereof. In certain embodiments of thepresent invention an “effective amount” of the compound orpharmaceutical composition is that amount effective for treating aproliferative, inflammatory, or cardiovascular disorder, or is thatamount effective for treating cancer. In other embodiments, an“effective amount” of a compound is an amount which inhibits binding ofPI3K and thereby blocks the resulting signaling cascades that lead tothe abnormal activity of growth factors, receptor tyrosine kinases,protein serine/threonine kinases, G protein coupled receptors andphospholipid kinases and phosphatases.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating the disease. The exact amountrequired will vary from subject to subject, depending on the species,age, and general condition of the subject, the severity of the disorder,the particular agent, its mode of administration, and the like. Thecompounds of the invention are preferably formulated in dosage unit formfor ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the patient to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disease being treated and theseverity of the disease; the activity of the specific compound employed;the specific composition employed; the age, body weight, general health,sex and diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed, and like factors well known in themedical arts. The term “patient”, as used herein, means an animal,preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), buccally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

While one or more of the inventive compounds may be used in anapplication of monotherapy to treat a disorder, disease or symptom, theyalso may be used in combination therapy, in which the use of aninventive compound or composition (therapeutic agent) is combined withthe use of one or more other therapeutic agents for treating the sameand/or other types of disorders, symptoms and diseases. Combinationtherapy includes administration of the therapeutic agents concurrentlyor sequentially. Alternatively, the therapeutic agents can be combinedinto one composition which is administered to the patient.

In one embodiment, the compounds of this invention are used incombination with other therapeutic agents. In other embodiments, acompound of the invention is administered in conjunction with atherapeutic agent selected from the group consisting of cytotoxicagents, radiotherapy, and immunotherapy. It is understood that othercombinations may be undertaken while remaining within the scope of theinvention.

Those additional agents may be administered separately from a providedcombination therapy, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a combination therapy, the two therapeuticagents may be submitted simultaneously, sequentially or within a periodof time from one another normally within about one through twelve hoursfrom one another. For example, one therapeutic agent can be administeredwithin about one, two, three, four, five, six, seven, eight, nine, ten,eleven, or twelve hours from the other therapeutic agent or agents usedin the combination therapy.

Combination therapy can be used for any of the therapeutic indicationsdescribed herein. In one aspect, the invention provides a method,wherein the method is a combination therapy further comprisingadministering to the subject (1) a pharmaceutically active ingredient orexposing the subject to (2) cognitive behavioral therapy (CBT), (3)psychotherapy, (4) behavioral exposure treatments, (5) virtual realityexposure (VRE) or (6) cognitive remediation therapy or (7) anycombination thereof. In one aspect, the invention provides a combinationtherapy for treating, alleviating, and/or preventing post-traumaticstress disorder (PTSD) or Alzheimer's disease in a subject comprisingadministering to the subject in need thereof an effective amount of (1)a compound of the invention or a pharmaceutically acceptable salt,hydrate, solvate, or prodrug thereof and (2) a pharmaceutically activeingredient administered selected from Aricept®, memantine, andgalantamine.

In one aspect, the invention provides a method of treating extinctionlearning disorders in a subject in need thereof comprising administeringto the subject an effective amount of a compound of the invention or apharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.In one aspect, the extinction learning disorder is fear extinctiondeficit. In one aspect, the extinction learning disorder ispost-traumatic stress disorder. In one aspect, the method is acombination therapy for treating extinction learning disorders in asubject in need thereof comprising administering to the subject (1) aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt, hydrate, solvate, or prodrug thereof and (2) exposingthe subject to cognitive behavioral therapy (CBT), psychotherapy,behavioral exposure treatments, virtual reality exposure (VRE) orcognitive remediation therapy.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a combination ofthe present invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form.

Another aspect of the invention relates to inhibiting HDAC activity in abiological sample or a patient, which method comprises administering tothe patient, or contacting said biological sample with a compounddescribed herein, or a composition comprising said compound. The term“biological sample”, as used herein, generally includes in vivo, invitro, and ex vivo materials, and also includes, without limitation,cell cultures or extracts thereof; biopsied material obtained from amammal or extracts thereof; and blood, saliva, urine, feces, semen,tears, or other body fluids or extracts thereof.

Still another aspect of this invention is to provide a kit comprisingseparate containers in a single package, wherein the inventivepharmaceutical compounds, compositions and/or salts thereof are used incombination with pharmaceutically acceptable carriers to treatdisorders, symptoms and diseases where HDAC plays a role.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

General Information

Spots were visualized by UV light (254 and 365 nm). Purification bycolumn and flash chromatography was carried out using silica gel(200-300 mesh). Solvent systems are reported as the ratio of solvents.

NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. ¹Hchemical shifts are reported in δ values in ppm with tetramethylsilane(TMS, =0.00 ppm) as the internal standard.

LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 massspectrometer with ESI (+) ionization mode.

Example 1. Synthesis of Compound 100

Synthesis of 153-1. A solution of 153-0 (2.00 g, 8.4 mmol) and (NH₄)₂CO₃(4.00 g, 42 mmol) in DMF (20 mL) was heated to 90° C. overnight. Themixture was cooled to room temperature and poured into water (100 mL).The precipitate was filtered off and washed with the mixture of diethylether (Et₂O) and petroleum ether (PE; Et₂O:PE=1:1) to give 153-1 (1.50g, 76%) as a yellow solid.

Synthesis of 153-2. To a mixture of 153-1 (1.40 g, 6.0 mmol),4-fluorophenylboronic acid (920 mg, 7.7 mmol) and Cs₂CO₃ (5.83 g, 18.0mmol) in dioxane/H₂O (30 mL/6 mL) was added Pd(PPh₃)₄ (693 mg, 0.6 mmol)under N₂ atmosphere. The mixture was stirred at 95° C. for 2 hours andthen concentrated in vacuo. The residue was dissolved with ethyl acetate(EtOAc; 100 mL) and the solution was washed with brine (30 mL×3). Theorganic layer was dried over anhydrous Na₂SO₄ and then concentrated invacuo. The residue was purified by column chromatography on silica gel(PE:EtOAc=5:1˜3:1) to give 153-2 (1.10 g, 74%) as a yellow solid.

Synthesis of 153-3. To a solution of 153-2 (260 mg, 1.0 mmol) andtrimethylamine (TEA; 810 mg, 8.0 mmol) in dichloromethane (DCM; 15 mL)was added triphosgene (330 mg, 1.1 mmol) under ice bath. The solutionwas warmed to room temperature and continued to stir for 3 h. TEA (200mg, 2.0 mmol) and SM0 (210 mg, 1.1 mmol) was then added. The resultingsolution was heated at 50° C. for 2 hours. After the reaction wascompleted according to LCMS, the solution was diluted with DCM (15 mL)and the resulting solution was washed with brine (10 mL×3). The organiclayer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜30:1) to give 153-3 (200 mg, 50%) as a yellow solid.

Synthesis of 100. A mixture of 153-3 (200 mg, 0.5 mmol) and Pd/C (60 mg)in MeOH/THF (5 mL/5 mL) was stirred at room temperature for 2 hoursunder H₂ atmosphere. Pd/C was then removed by the filtration through thecelite. The filtrate was concentrated and the residue was recrystallizedwith MTBE to give 100 (60 mg, 33%) as a yellow solid.

Compounds 114, 116 and 119 were synthesized in a similar manner usingthe appropriately substituted amine variant of 100.

Compound 114. 120 mg, 50%, a white solid.

Compound 116. 160 mg, 54%, a white solid.

Compound 119. 14 mg, 8%, a white solid.

Example 2. Synthesis of Compound 101

Synthesis of 155-1. To a mixture of 155-0 (869 mg, 5.1 mmol) andphenylhydrazine (500 mg, 4.6 mmol) in AcOH/H₂O (10 mL/2 mL) was addedNaOAc.3H₂O (1.40 g, 10.0 mmol). The reaction mixture was stirred at 130°C. for 30 min under microwave. The mixture was allowed to cool to roomtemperature and ice-water was added. The precipitate was collected byfiltration and washed with the mixture of Et₂O and PE (Et₂O:PE=1:1) togive 155-1 (1.03 g, 96%) as a yellow solid.

Synthesis of 155-1a. To a stirred solution of 155-1 (1.00 g, 4.3 mmol)in aq. HBr (48%, 5 mL) was added a solution of NaNO₂ (310 mg, 4.5 mmol)in H₂O (3 mL) dropwise under ice bath. The solution was stirred at thistemperature for 1.5 hours and a solution of CuBr (443 mg, 3.0 mmol) inaq. HBr (48%, 5 mL) was then added dropwise. The resulting mixture wasstirred at 60° C. for another 1.5 hours. After the reaction wascompleted according to LCMS, the mixture was poured into water (40 mL)and the resultant was extracted with EtOAc (20 mL×3). The combinedorganic layer was washed with H₂O (20 mL×3), dried over anhydrous Na₂SO₄and concentrated to give 155-1a (1.20 g, 94%) as a brown solid, whichwas used directly to next step without further purification.

Synthesis of 155-2. To a solution of 155-1a (750 mg, 2.5 mmol),diphenylmethanimine (508 mg, 2.8 mmol), Xantphos (148 mg, 0.25 mmol) andCs₂CO₃ (2.50 g, 7.6 mmol) in dioxane (15 mL) was added Pd(OAc)₂ (115 mg,0.51 mmol) under N₂ atmosphere in a seal tube. The mixture was heated at130° C. for 3 hours under microwave. The resulting mixture wasconcentrated in vacuo. The residue was poured into H₂O (50 mL) and theresultant was extracted with EtOAc (30 mL×3). The combined organic layerwas washed with brine (30 mL×3), dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (PE:EA=10:1˜2:1) to give 155-2 (500 mg, 50%) as a yellowoil.

Synthesis of 155-3. To a solution of 155-2 (150 mg, 0.38 mmol) inmethanol (MeOH; 4 mL) was added aq. KOH (2 mL) dropwise under ice bath.The mixture was stirred at 60° C. for 4 hours and then poured into water(40 mL). The resultant was washed with EtOAc (20 mL) and the aqueouslayer was adjusted to pH=5 with diluted HCl solution. The mixture wasextracted with EtOAc (30 mL×3). The combined organic layer was washedwith brine (30 mL×3), dried over anhydrous Na₂SO₄ and concentrated invacuo to give 155-3 (96 mg, 69%) as a yellow solid.

Synthesis of 155-4. To a solution of 155-3 (560 mg, 1.5 mmol) in toluene(7 mL) was added TEA (0.64 mL, 4.6 mmol) and DPPA (840 mg, 3.0 mmol)successively. The resulting mixture was stirred at room temperature for2 h. After the reaction was completed according to LCMS, the mixture waswashed with water (7 mL) and dried over anhydrous Na₂SO₄. The resultingsolution was concentrated to give 155-4 (510 mg, 85%) as a yellow solid,which was used directly to next step without further purification.

Synthesis of 155-5. A solution of 155-4 (390 mg, 1.3 mmol) in toluene (7mL) was heated at 80° C. for 4 hours. After cooling to room temperature,TEA (0.55 mL, 3.9 mmol) and SM0 (175 mg, 0.91 mmol) were addedsuccessively. The resulting mixture was stirred at 50° C. for 16 hours.After the reaction was completed according to LCMS, the mixture wasdiluted with EtOAc (30 mL). The resultant was washed with water (20mL×3). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (DCM:MeOH=20:1) to give 155-5 (130 mg, 21%) as a yellowsolid.

Synthesis of 101. To a suspension of 155-5 (120 mg, 0.25 mmol) in EtOAc(5 mL) was added conc. HCl (0.1 mL). The mixture was stirred at roomtemperature for 5 min and then concentrated in vacuo. The residue waspurified by Pre-HPLC to give 101 (30 mg, 38%) as a white solid.

Example 3. Synthesis of Compound 102

Synthesis of 158-1. To a mixture of 155-0 (2.00 g, 11.8 mmol) and(4-fluorophenyl)hydrazine (1.35 g, 10.7 mmol) in AcOH/H₂O (30 mL/6 mL)was added NaOAc*3H₂O (3.03 g, 23.3 mmol). The reaction mixture wasstirred at 130° C. for 30 minutes under microwave. After cooling to roomtemperature, ice-water was added. The precipitate was collected byfiltration and washed with the mixture of Et₂O and PE (Et₂O:PE=1:1) togive 158-1 (2.00 g, 75%) as a yellow solid.

Synthesis of 158-2. To a stirred solution of 158-1 (1.40 g, 5.6 mmol) inTHF (20 mL) was added NaH (269 mg, 6.7 mmol) under ice bath. Thesolution was stirred at this temperature for 1 hour and a solution ofbenzyl chloroformate (CbzCl; 1.14 g, 6.7 mmol) in THF (8 mL) was thenadded dropwise. The resulting mixture was stirred at room temperaturefor another 2 h. After the reaction was completed according to LCMS, themixture was diluted with water (40 mL). The resultant was extracted withEtOAc (30 mL×3). The combined organic layer was washed with brine (30mL×3), dried over Na₂SO₄ and concentrated in vacuo to give 158-2 as acrude product, which was used directly to next step without furtherpurification.

Synthesis of 158-3. A mixture of 158-2 (crude) and LiOH*H₂O (470 mg,11.2 mmol) in THF (30 mL) was stirred at 60° C. for 4 hours. The solventwas removed in vacuo. The residue was diluted with water (20 mL) and theresultant was washed with EtOAc (20 mL). The aqueous layer was adjustedto pH=5 with 2N HCl solution. The resulting mixture was extracted withEtOAc (30 mL×3). The combined organic layer was washed with brine (30mL×3), dried over Na₂SO₄ and concentrated to give 155-3 (0.90 g, 45%over two step) as a yellow solid.

Synthesis of 158-4. A mixture of 158-3 (532 mg, 1.5 mmol) and TEA (454mg, 4.5 mmol) in DCE (10 mL) was stirred at room temperature for 20 min.Diphenylphosphoryl azide (DPPA; 825 mg, 3 mmol) was then added dropwise.The mixture was stirred at 45° C. for 3 h. After cooling to roomtemperature, the resulting mixture was washed with water, dried overNa₂SO₄ and concentrated (below 40° C.) to give 158-4 (600 mg) as a crudeproduct, which was used directly for next step without furtherpurification.

Synthesis of 158-5. A solution of 158-4 (600 mg, 1.5 mmol) in toluene(10 mL) was stirred at 80° C. for 2 h. After cooling to roomtemperature, TEA (454 mg, 4.5 mmol) and SM0 (286 mg, 1.5 mmol) was addedsuccessively. The resulting mixture was stirred at 50° C. for 4 h. Thesolvent was removed and the residue was purified by columnchromatography on silica gel (DCM:MeOH=50:1˜5:1) to give 158-5 (200 mg,28%) as a yellow solid.

Synthesis of 102. A mixture of 158-5 (200 mg, 0.42 mmol) and Pd/C (60mg) in MeOH (15 mL) was stirred at room temperature overnight under H₂atmosphere. Pd/C was then removed by the filtration through the celite.The filtrate was concentrated in vacuo and the residue was purified byPre-HPLC to give (35 mg, 25%) as a yellow solid.

Compound 103 was synthesized in a similar manner using the appropriatelysubstituted amine variant of 102.

Compound 103. 10 mg, 7%, a white solid.

Example 4. Synthesis of Compound 104

Synthesis of 224-1. To a solution of 155-0 (20.0 g, 116.3 mmol) inpyridine (400 mL) was added ethyl carbonochloridate (15.1 g, 139.5 mmol)dropwise under ice bath. The reaction mixture was stirred at roomtemperature for 2 h. The solvent was removed in vacuo. The residue wasdissolved in EtOAc (200 mL) and the resulting solution was washed withwater (30 mL×5). The organic layer was dried over Na₂SO₄ andconcentrated to give 224-1 (20.0 g, 70%) as a yellow solid.

Synthesis of 224-2. To a stirred solution of 224-1 (17.0 g, 69.7 mmol)in con.H₂SO₄ (80 mL) was added con.HNO₃ (10 mL) under ice bath. Themixture was stirred 40° C. for 48 h. After cooling to room temperature,the mixture was poured into ice water (400 mL). The precipitate wascollected by filtration and dried to give 224-2 (4.80 g, 24%) as ayellow solid.

Synthesis of 224-3. A mixture of 224-2 (4.80 g, 16.7 mmol) and KOH (1.87g, 33.4 mmol) in EtOH/H₂O (50 mL/50 mL) was stirred at 95° C. for 2 h.The volatile solvent was removed in vacuo. The aqueous solution waswashed with EtOAc (20 mL) and then adjusted to pH=5 with 2N HClsolution. The precipitate was collected by filtration and dried to give224-3 (2.70 g, 75%) as a yellow solid.

Synthesis of 224-4. To a mixture of 224-3 (1.50 g, 6.0 mmol),4-fluorophenylboronic acid (1.01 g, 7.2 mmol) and Cs₂CO₃ (3.91 g, 12.0mmol) in dioxane/H₂O (30 mL/6 mL) was added Pd(PPh₃)₄ (693 mg, 0.6 mmol)under N₂ atmosphere. The mixture was stirred at 95° C. for 2 hours andthen concentrated in vacuo. The residue was dissolved in EtOAc (100 mL)and the resulting solution was washed with brine (30 mL×3). The organiclayer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜50:1) to give 224-4 (1.00 g, 72%) as a yellow solid.

Synthesis of 224-5. To a solution of 224-4 (233 mg, 1.0 mmol) and TEA(810 mg, 8.0 mmol) in DCM (15 mL) was added triphosgene (330 mg, 1.1mmol) under ice bath. The solution was warmed to room temperature andcontinued to stir for 3 h. TEA (200 mg, 2.0 mmol) and SM1 (122 mg, 1.1mmol) was then added. The reaction mixture was heated at 50° C. for 2 h.After the reaction was completed according to LCMS, the solution wasdiluted with DCM (15 mL) and the resulting solution was washed withbrine (10 mL×3). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (DCM:MeOH=100:1˜20:1) to give 224-5 (180 mg, 49%) as ayellow solid.

Synthesis of 104. A mixture of 224-5 (180 mg, 0.5 mmol) and Pd/C (60 mg)in MeOH (5 mL) was stirred at room temperature for 2 hours under H₂atmosphere. Pd/C was then removed by filtration through the celite. Thefiltrate was concentrated and the residue was recrystallized with MTBEto give 104 (60 mg, 36%) as a yellow solid.

Example 5. Synthesis of Compound 105

Synthesis of 323-1. To a mixture of 323-0 (1.00 g, 4.6 mmol),4-fluorophenylboronic acid (773 mg, 5.5 mmol) and Cs₂CO₃ (3.00 g, 9.2mmol) in dioxane/H₂O (20 mL/4 mL) was added Pd(PPh₃)₄ (531 mg, 0.5 mmol)under N₂ atmosphere. The mixture was stirred at 95° C. for 2 hours andthen concentrated in vacuo. The residue was dissolved with EtOAc (60 mL)and the resulting solution was washed with brine (20 mL×3). The organiclayer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜50:1) to give 323-1 (1.00 g, 93%) as a yellow solid.

Synthesis of 323-2. To a solution of 323-1 (300 mg, 1.3 mmol) and TEA(1.05 g, 10.4 mmol) in DCM (15 mL) was added triphosgene (425 mg, 1.4mmol) under ice bath. The solution was warmed to room temperature andcontinued to stir for 3 h. TEA (263 mg, 2.6 mmol) and pyrrolidine (102mg, 1.4 mmol) was then added. The reaction mixture was heated at 50° C.for 2 h. After the reaction was completed according to LCMS, thesolution was diluted with DCM (15 mL) and the resulting solution waswashed with brine (10 mL×3). The organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (DCM:MeOH=100:1˜20:1) to give 323-2 (130mg, 30%) as a yellow solid.

Synthesis of 105. A mixture of 323-2 (130 mg, 0.4 mmol) and Pd/C (50 mg)in MeOH (5 mL) was stirred at room temperature for 2 hours under H₂atmosphere. Pd/C was then removed by filtration through the celite. Thefiltrate was concentrated in vacuo and the residue was purified byPre-HPLC to give 105 (25 mg, 21%) as a yellow solid.

Compound 108 was synthesized in a similar manner using the appropriatelysubstituted amine variant of 105.

Compound 108. 15 mg, 24%, a white solid.

Example 6. Synthesis of Compound 106

Synthesis of 528-1. To a solution of 323-1 (100 mg, 0.4 mmol) inpyridine (3 mL) was added POCl₃ (91 mg, 0.6 mmol) dropwise under icebath. The mixture was warmed to room temperature and stirred overnight.After the reaction was completed according to LCMS, the mixture waspoured into ice water (10 mL). The precipitate was collected byfiltration and dried to give 528-1 (60 mg, 40%) as a yellow solid.

Synthesis of 106. A mixture of 528-1 (60 mg, 0.2 mmol) and Pd/C (20 mg)in MeOH (3 mL) was stirred at room temperature for 2 hours under H₂atmosphere. Pd/C was removed by filtration through the celite. Thefiltrate was concentrated in vacuo and the residue was purified byPre-HPLC to give 106 (13 mg, 24%) as a white solid.

Example 7. Synthesis of Compound 107

Synthesis of 464-1. To a mixture of 464-0 (2.00 g, 11.6 mmol),4-fluorophenylboronic acid (1.95 g, 13.9 mmol) and K₂CO₃ (3.20 g, 23.2mmol) in dioxane/H₂O (40 mL/8 mL) was added Pd(PPh₃)₄ (1.4 g, 1.2 mmol)under N₂ atmosphere. The mixture was stirred at 95° C. for 2 hours andthen concentrated in vacuo. The residue was dissolved with EtOAc (100mL) and the resulting solution was washed with brine (30 mL×3). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜50:1) to give 464-1 (1.70 g, 63%) as a yellow solid.

Synthesis of 501-1. To a solution of 464-1 (90 mg, 0.4 mmol) inN,N-dimethylformamide (DMF; 3 mL) was added NaH (32 mg, 0.8 mmol) underice bath. The solution was stirred for 1 hour at the same temperatureand pyrrolidine-1-carbonyl chloride (67 mg, 0.5 mmol) was then added.The resulting solution was warmed to room temperature and continued tostir for 2 h. After the reaction was completed according to LCMS, thereaction mixture was poured into ice water (10 mL). The precipitate wascollected by filtration and dried to give 501-1 (85 mg, 64%) as a yellowsolid.

Synthesis of 107. A mixture of 501-1 (85 mg, 0.3 mmol) and Pd/C (20 mg)in MeOH (5 mL) was stirred at room temperature for 2 hours under H₂atmosphere. Pd/C was removed by filtration through the celite. Thefiltrate was concentrated and the residue was purified by Pre-HPLC togive 107 (20 mg, 26%) as a white solid.

Compounds 111 and 120 were synthesized in a similar manner using theappropriately substituted amine variant of 107.

Compound 111. 20 mg, 28%, a white solid.

Compound 120. 14 mg, 38%, a yellow solid.

Example 8. Synthesis of Compound 109

Synthesis of 505-1. To a solution of 464-1 (300 mg, 1.3 mmol) inpyridine (5 mL) was added POCl₃ (297 mg, 2.0 mmol) dropwise under icebath. The solution was warmed to room temperature and stirred overnight.After the reaction was completed according to LCMS, the mixture waspoured into ice water (10 mL). The precipitate was collected byfiltration and dried to give 505-1 (60 mg, 13%) as a yellow solid.

Synthesis of 109. A mixture of 505-1 (60 mg, 0.2 mmol) and Pd/C (20 mg)in MeOH/THF (3 mL/3 mL) was stirred at room temperature for 2 hoursunder H₂ atmosphere. Pd/C was removed by filtration through the celite.The filtrate was concentrated and the residue was purified by Pre-HPLCto give 109 (20 mg, 31%) as a white solid.

Example 9. Synthesis of Compound 110

Synthesis of 553-1. To a mixture of 553-0 (2.00 g, 11.5 mmol),4-fluorophenylboronic acid (1.93 mg, 13.8 mmol) and K₂CO₃ (3.00 g, 9.2mmol) in dioxane (40 mL) was added Pd(OAc)₂ (271 mg, 1.2 mmol) and1,1′-Bis(di-tert-butylphosphino)ferrocene (D-t-BPF; 284 mg, 0.6 mmol)under N₂ atmosphere. The mixture was stirred at 100° C. for 2 hours andthen concentrated in vacuo. The residue was dissolved with EtOAc (100mL) and the resulting solution was washed with brine (30 mL×3). Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo.The residue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜30:1) to give 553-1 (500 mg, 19%) as a yellow solid.

Synthesis of 553-2. To a solution of 553-1 (100 mg, 0.4 mmol) and TEA(323 mg, 3.2 mmol) in DCM (15 mL) was added triphosgene (149 mg, 0.5mmol) under ice bath. The solution was warmed to room temperature andstirred for 3 h. TEA (81 mg, 0.8 mmol) and pyrrolidine (36 mg, 0.5 mmol)was then added. The resulting solution was heated at 50° C. for 2 h.After the reaction was completed, the mixture was diluted with DCM (15mL) and the resulting solution was washed with brine (10 mL×3). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜10:1) to give 553-2 (60 mg, 45%) as a yellow solid.

Synthesis of 110. A mixture of 553-2 (60 mg, 0.2 mmol) and Pd/C (20 mg)in MeOH (5 mL) was stirred at room temperature for 2 hours under H₂atmosphere. Pd/C was removed by filtration through the celite. Thefiltrate was concentrated and the residue was was recrystallized withMTBE to give 110 (40 mg, 73%) as a yellow solid.

Compound 121 was synthesized in a similar manner using the appropriatelysubstituted amine variant of 110.

Compound 121. 24 mg, 43%, a yellow solid.

Example 10. Synthesis of Compound 112

Synthesis of 728-1. To a solution of 728-0 (4.65 g, 35.7 mmol) in DMF(30 mL) was added a solution of NBS (6.36 g, 35.7 mmol) in DMF (20 mL)at 0° C. The resulting solution was stirred at the same temperature for30 minutes, warmed to room temperature and continued to stir for 1 h.The solution was diluted with EtOAc (100 mL). The resulting solution waswashed with brine (30 mL×3) and dried over anhydrous Na₂SO₄. Thecombined organic layer was concentrated in vacuo to give 728-1 (6.5 g,93%) as a yellow solid.

Synthesis of 728-2. A mixture of 728-1 (2.7 g, 11.5 mmol),4-fluorobenzeneboronic acid (1.93 g, 13.8 mmol), Cs₂CO₃ (11.2 g, 34.5mmol), and Pd(PPh₃)₄ in dioxane/H₂O (45 mL/15 mL) was purged by N₂ andstirred at 95° C. for 3 h. The mixture was concentrated in vacuo. Theresidue was dissolved with EtOAc (50 mL) and the resulting solution waswashed with brine (15 mL×3). The organic layer was dried over anhydrousNa₂SO₄ and then concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (PE:EtOAc=10:1˜4:1) give 728-2 (2.6g, 90%) as a yellow solid.

Synthesis of 728-3. A mixture of 728-2 (1.5 g, 6.0 mmol), (Boc)₂O (2.87g, 13.2 mmol), DMAP (732 mg, 6.0 mmol) in THF (50 mL) was stirred at 80°C. for 3 h. After the reaction was completed according to LCMS, themixture was diluted with water (150 mL). The resulting mixture wasextracted with EtOAc (50 mL×3). The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(PE:EtOAc=20:1˜10:1) to give 728-3 (2.0 g, 74%) as a white solid.

Synthesis of 728-4. A solution of 728-3 (2.0 g, 4.4 mmol) and Pd/C (200mg) in MeOH (30 mL) was stirred at room temperature for 3 hours under H₂atmosphere. Pd/C was removed by filtration through the celite. Thefiltrate was concentrated to give 728-4 (1.5 g, 81%) as a yellow solid.

Synthesis of 728-5. To a solution of 728-4 (200 mg, 0.5 mmol), TEA (404mg, 4.0 mmol) in DCM (10 mL) was added triphosgene (169 mg, 0.6 mmol)under ice bath. The solution was warmed to room temperature andcontinued to stir for 1 h. TEA (202 mg, 2.0 mmol) and pyrrolidine (50mg, 0.70 mmol) was then added. The resulting solution was heated at 50°C. for 2 h. After cooling to room temperature, the mixture was dilutedwith DCM (10 mL). The resulting solution was washed with brine (10mL×3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜20:1) to give 728-5 (205 mg, 81%) as a gray solid.

Synthesis of 112. A mixture of 728-5 (205 mg, 0.4 mmol) in HCl/EA (20mL) was stirred at room temperature for 2 h. The solvent was removedunder the reduced pressure. The residue was dissolved in water (3 mL)and adjusted to PH>7 by 1N NaOH solution. The resultant was extractedwith EtOAc (5 mL×3). The combined organic layer was washed with brine(10 mL×3), dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by Pre-HPLC to give 112 (90 mg, 71%) as a whitesolid.

Compounds 113 and 117 were synthesized by a similar procedure using anappropriately phenyl-substituted derivative of 112.

Compound 113. 130 mg, 45%, a white solid.

Compound 117. 70 mg, 86%, a white solid.

Example 11. Synthesis of Compound 115

Synthesis of 732-0. To a solution of SM2 (230 mg, 1.8 mmol) and acatalytic amount of DMF in THF (15 mL) was added (COCl)₂ (0.2 mL, 2.7mmol) dropwise under ice bath. The resulting mixture was stirred at roomtemperature for 1 hour and then concentrated in vacuo to afford 732-0(240 mg, 90%) as a yellow oil, which was used directly to next stepwithout further purification.

Synthesis of 732-1. To a solution of 153-2 (300 mg, 1.2 mmol) in DMF (12mL) was added NaH (144 mg, 3.6 mmol) under ice bath. The mixture waswarmed to room temperature and continued to stir for 30 min. Aftercooling to 0° C., a solution of 732-0 (265 mg, 1.8 mmol) in DMF (6 mL)was added dropwise. The resulting mixture was then warmed to roomtemperature and stirred for another 3 h. After the reaction wascompleted according to LCMS, the mixture was added to ice water (50 mL).The resultant was extracted with EtOAc (30 mL×3). The combined organiclayer was washed with brine (20 mL×3), dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (PE:EtOAc=10:1˜5:1) to give 732-1 (360 mg, 83%) as ayellow solid.

Synthesis of 115. A mixture of 732-1 (360 mg, 1.0 mmol) and Pd/C (72 mg)in MeOH/THF (25 mL/5 mL) was stirred at room temperature for 2 hoursunder H₂ atmosphere. Pd/C was removed by filtration through the celite.The filtrate was concentrated and the residue was purified by Pre-HPLCto give 115 (190 mg, 57%) as a white solid.

Compound 118 was synthesized by a similar procedure using anappropriately phenyl-substituted derivative of 115.

Compound 118. 72 mg, 52%, a white solid.

Example 12. Synthesis of Compound 122

Synthesis of 156-1. To a solution of nitromethane (4.67 g, 77.0 mmol) inDMF (50 mL) was added DMF-DMA (6.72 g, 92.0 mmol). The mixture wasstirred at 45° C. for 45 min. Then the mixture was cooled to roomtemperature and poured into EtOAc (100 mL). The resultant was washedwith water (50 mL×3), dried over anhydrous Na₂SO₄ and concentrated invacuo to give 156-1 (3.50 g, 39%) as a yellow oil, which was useddirectly to next step without further purification.

Synthesis of 156-2. A solution of NaNO₂ (7.24 g, 105 mmol) in H₂O (15ml) cooled to 0° C. was slowly added to a mixture of aniline (9.3 g, 100mmol), H₂O (100 ml) and conc. HCl (23 ml) with vigorous stirring. Theprepared diazo solution was added drop by drop at 0-5° C. to a solutionof ethyl 2-chloro-3-oxobutanoate (16.4 g, 100 mmol) and sodium acetate(12.3 g, 150 mmol) in 10 mL of ethanol containing minimal amount ofwater. The reaction mixture was continued to stir for 1 h. The obtainedprecipitate was filtered off, washed with water and dried in the openair to give 156-2 (11.3 g, 50%) as a yellow solid, which was useddirectly to next step without further purification.

Synthesis of 156-3. To a stirred mixture of 156-1 (2.17 g, 19.0 mmol)and 156-2 (8.48 g, 37 mmol) in CHCl₃ (110 mL) was added TEA (3.79 g, 37mmol). The resulting mixture was heated to reflux for 24 hours and thenconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (PE:EA=10:1) to give 156-3 (3.7 g, 76%) as a brown solid.

Synthesis of 156-4. To a solution of 156-3 (1.85 g, 7.1 mmol) in THF (33mL) was added a solution of LiOH.H₂O (893 mg, 21 mmol) in water (11 mL)dropwise under ice bath. Then MeOH (11 mL) was added. The mixture wasstirred at room temperature for 3 h. The volatile solvent was removed invacuo and the aqueous layer was adjusted to pH=4 with 2N HCl solution.The resultant was extracted with EtOAc (30 mL×3). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM:MeOH=50:1˜15:1) to give 156-4 (780 mg, 48%) as a brown solid.

Synthesis of 156-5. To a solution of 156-4 (400 mg, 1.7 mmol) and TEA(0.45 mL, 3.3 mmol) in acetone (13 mL) was added ethyl carbonochloridate(370 mg, 3.4 mmol) dropwise under ice bath. The mixture was stirred atthis temperature for 30 min. Then a solution of NaN₃ (212 mg, 3.3 mmol)in H₂O (1 mL) was added dropwise and the reaction mixture was stirred at0° C. for 2 h. After the reaction was completed according to LCMS, thesolvent was removed in vacuo and the residue was diluted with DCM (30mL). The resulting mixture was washed with water (20 mL). The organiclayer was dried over Na₂SO₄ and concentrated to give 156-5 (370 mg, 83%)as a brown solid, which was used directly to next step without furtherpurification.

Synthesis of 156-5a. A mixture of 156-5 (580 mg, 2.2 mmol), t-BuOH (20mL) and dioxane (5 mL) was stirred at 90° C. for 2 h. Then the solventwas removed in vacuo to give 156-5a (530 mg, 77%) as a yellow solid.

Synthesis of 156-5b. To a solution of 156-5a (680 mg, 2.2 mmol) in DCM(17 mL) was added TFA (3.3 mL, 45 mmol) dropwise under ice bath. Themixture was stirred at room temperature for 3 hours and the solvent wasremoved in vacuo. The residue was diluted with hexanes/EA/DCM (75 mL/15mL/10 mL). The formed precipitate was filtered, washed with the abovesolvent mixture to give a yellow solid. The solid was diluted with DCM(20 mL) and the mixture was adjusted to PH=8 with TEA. The resultant waswashed with water (20 mL). The organic layer was dried over anhydrousNa₂SO₄ and concentrated to give 156-5b (410 mg, 90%) as a yellow solid.

Synthesis of 156-6. To a solution of 156-5b (300 mg, 1.5 mmol) and TEA(1.65 mL, 12.0 mmol) in DCM (18 mL) was added triphosgene (480 mg, 1.6mmol) successively under ice bath. The mixture was stirred at 35° C. for3 h. After cooling to 0° C., a solution of SM-0 (312 mg, 1.6 mmol) andTEA (0.8 mL, 5.9 mmol) in DCM (6 mL) was added dropwise. The resultingmixture was heated to 50° C. and stirred for another 2 h. After coolingto room temperature, the mixture was diluted with DCM (10 mL). Theresultant was washed with brine (10 mL×3). The organic layer was driedover anhydrous Na₂SO₄ and then concentrated in vacuo. The residue waspurified by column chromatography on silica gel (DCM:MeOH=100:1˜20:1) togive 156-6 (230 mg, 45%) as a yellow solid.

Synthesis of 122 (T-156). A mixture of 156-6 (230 mg, 0.67 mmol) andPd/C (45 mg) in MeOH (15 mL) was stirred at room temperature for 4 hoursunder H₂ atmosphere. Pd/C was removed by filtration through the celite.The filtrate was concentrated and the residue was purified by Pre-HPLCto give 122 (T-156) (25 mg, 12%) as a white solid. Example 13. Synthesisof Compound 143.

Synthesis of 143-A. To a solution of tert-butyl5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.00 g, 4.7 mmol)in DCM (10 mL) was added TFA (10.8 g, 47.4 mmol) dropwise. Then thesolution was stirred at room temperature for 1 h. The solution wasconcentrated in vacuo to give 1450-A (0.99 g, 94%) as a colorless oil.

Synthesis of 143-B. A mixture of 6-chloro-3-nitropyridin-2-amine (10.0g, 57.6 mmol), 4-fluorophenylboronic acid (8.87 g, 63.4 mmol) and Cs₂CO₃(37.56 g, 115.2 mmol) in dioxane/H₂O (200 mL/20 mL) was added Pd(PPh₃)₄(2.44 g, 2.9 mmol) under N₂ atmosphere. The mixture was stirred at 95°C. for 2 h and then concentrated in vacuo. The residue was dissolvedwith EtOAc (200 mL) and the solution was washed with brine (100 mL×3).The organic layer was dried over anhydrous Na₂SO₄ and then concentratedin vacuo. The residue was purified by column chromatography on silicagel (PE:EtOAc=5:1˜3:1) to give 143-B (11.2 g, 83%) as a yellow solid

Synthesis of 143-C. A stirred solution of 143-B (3.0 g, 13.0 mmol) inpyridine (60 mL) was added phenyl carbonochloridate (4.45 g, 28.5 mmol)dropwise. After the addition was completed, the mixture was hated to 50°C. for 4 h. The mixture was concentrated in vacuo. The residue waspurified by column chromatography on silica gel (PE:EtOAc=8:1˜3:1) togive 143-C (5.2 g, 84%) as a yellow solid.

Synthesis of 143-D. A mixture of 143-A (0.99 g, 4.2 mmol) and 143-C (0.9g, 1.9 mmol) in acetonitrile (20 mL) was stirred at 50° C. for 30 min,then Na₂CO₃ (1.82 g, 19.0 mmol) was added into above mixture and stirredat 50° C. for 2 h. The mixture was cooled to room temperature. Na₂CO₃was removed by filtered, the filtrate was concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM:MeOH=50:1˜10:1) to give 143-D (1.47 g, 91%) as a yellow solid.

Synthesis of 143-E. To a mixture of 143-D (150 mg, 0.39 mmol) andazetidine hydrochloride (73 mg, 0.78 mmol) in DCE (5 mL) was addedacetic acid (1 drop) and stirred at 50° C. for 2 h, then NaBH(OAc)₃ (165mg, 0.78 mmol) was added into above mixture. Then the mixture wasstirred at 50° C. for 2 h. When the mixture was cooled to roomtemperature. The mixture was diluted with water (15 mL) and extractedwith DCM (10 mL×3). The combined organic layer was washed with brine (10mL×3), dried over anhydrous Na₂SO₄ and then concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜20:1) to give 143-E (80 mg, 48%) as a yellow solid.

Synthesis of 143. A mixture of 143-E (80 mg, 0.19 mmol) and Pd/C (80 mg)in MeOH (5 mL) was stirred at room temperature for 30 min under H₂atmosphere. Pd/C was removed by filtration through Celite. The filtratewas concentrated in vacuo and the residue was purified by Pre-TLC(DCM:MeOH=10:1) to give 143 (40 mg, 53%) as a light yellow solid.

Compounds 172, 179, 181, 237 and 238 was synthesized in a similar mannerusing the appropriately substituted amine variant of 143.

Compound 172. 100 mg, 60%, a white solid.

Compound 179. 60 mg, 43%, a white solid.

Compound 181. 18 mg, 19%, a white solid.

Compound 188. 40 mg, 41%, a white solid.

Compound 237. 8 mg, 45%, a light yellow solid.

Compound 248. 30 mg, 54%, a light yellow solid.

Compound 189 was synthesized in a similar manner using furan-2-ylboronicacid and the appropriately substituted amine variant of 143.

Compound 189. 27 mg, 19%, a yellow solid.

Compound 191 was synthesized in a similar manner using phenylboronicacid and the appropriately substituted amine variant of 143.

Compound 191. 80 mg, 67%, a yellow solid.

Example 14. Synthesis of Compound 123

Synthesis of 123-A. To a solution of 4-nitro-1H-pyrazole-3-carboxylicacid (8.00 g, 50.1 mmol) in MeOH (160 mL) was added SOCl₂ (11.92 g,100.2 mmol) dropwise under ice bath. Then the solution was stirred atroom temperature overnight. The solution was concentrated in vacuo togive 123-A (8.70 g, 84%) as a white solid.

Synthesis of 123-B. A mixture of 123-A (6.10 g, 29.4 mmol),4-fluorophenylboronic acid (5.43 g, 38.8 mmol), pyridine (9.29 g, 117.6mmol) and copper (II) acetate (8.03 g, 44.1 mmol) in DCM (120 mL) wasstirred at room temperature overnight. The residue was diluted with DCM(100 mL) and the solution was washed with brine (40 mL×3). The organiclayer was dried over anhydrous Na₂SO₄ and then concentrated in vacuo.The residue was purified by column chromatography on silica gel(PE:EtOAc=50:1˜10:1) to give 123-B (4.80 g, 62%) as a yellow solid.

Synthesis of 123-C. A mixture of 123-B (4.80 g, 18.1 mmol) and KOH (1.01g, 18.1 mmol) in THF/H₂O (40 mL/5 mL) was room temperature overnight.The solvent was removed in vacuo. The residue was dissolved with water(20 mL) and then adjusted to pH=3 with diluted HCl solution. Theprecipitate was collected by filtration and dried to give 123-B (4.00 g,88%) as a white solid.

Synthesis of 123-D. A mixture of 123-C (3.50 g, 13.9 mmol), DPPA (7.65g, 27.8 mmol), TEA (7.02 g, 69.5 mmol) and t-BuOH (20.57 g, 278.0 mmol)in dioxane (70 mL) was heated to reflux for 4 h under N₂ atmosphere. Thesolvent was removed in vacuo. The residue was dissolved with EtOAc (100mL) and the solution was washed with brine (40 mL×3). The organic layerwas dried over anhydrous Na₂SO₄ and then concentrated in vacuon to give123-D as a crude product.

Synthesis of 123-E. To a solution of 123-D (crude product from laststep) in DCM (14 mL) was added TFA (7 mL) dropwise under ice bath. Thenthe solution was stirred at room temperature 3 h. The solvent wasremoved in vacuo. The residue was dissolved with DCM (20 mL) and thenadjusted to pH>10 by NaOH (1 N) solution. The mixture was extracted withDCM (50 mL×3). The combined organic layer was washed with brine (50mL×3), dried over anhydrous Na₂SO₄ and then concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM:MeOH=100: 1-30:1) to give 123-E (2.30 g, 65% (two steps)) as ayellow solid.

Synthesis of 123-F. To a solution of 123-E (222 mg, 1.0 mmol) and TEA(808 mg, 8.0 mmol) in DCM (8 mL) was added triphosgene (297 mg, 1.0mmol) under ice bath. The solution was warmed to room temperature andcontinued to stir for 3 h. Then a solution of TEA (200 mg, 2.0 mmol) andSM5 (234 mg, 1.0 mmol) in DCM (4 mL) was added. The reaction mixture washeated at 50° C. for 2 h. After the reaction was completed according toLCMS, the solution was diluted with DCM (15 mL) and the resultingsolution was washed with brine (10 mL×3). The organic layer was driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (DCM:MeOH=100:1˜10:1) togive 123-F (200 mg, 41%) as a yellow solid.

Synthesis of 123. A mixture of 123-F (120 mg, 0.25 mmol) and Pd/C (30mg) in EtOAc/MeOH (8 mL/2 mL) was stirred at room temperature for 1 hunder H₂ atmosphere. Pd/C was then removed by filtration through thecelite. The filtrate was concentrated and the residue was purified byPre-TLC (DCM:MeOH=10:1) to give 123 (40 mg, 36%) as a white solid.

Compounds 124, 125, 130, 131, 132, 133, 134, 135, 136, 137 and 140 weresynthesized in a similar manner using the appropriately substitutedamine variant of 123.

Compound 124. 85 mg, 49%, a yellow solid.

Compound 125. 53 mg, 32%, a white solid.

Compound 130. 45 mg, 23%, a yellow solid.

Compound 131. 18 mg, 10%, a yellow solid.

Compound 132. 40 mg, 22%, a yellow solid.

Compound 133. 70 mg, 33%, a white solid.

Compound 134. 70 mg, 38%, a white solid.

Compound 136. 50 mg, 31%, a yellow solid.

Compound 137. 35 mg, 25%, a gray solid.

Compound 140. 60 mg, 37%, a gray solid.

Compounds 128, 129 and 142 were synthesized in a similar manner usingphenylboronic acid and the appropriately substituted amine variant of123.

Compound 128. 56 mg, 50%, a white solid.

Compound 129. 62 mg, 52%, a white solid.

Compound 142. 48 mg, 23%, a white solid.

Compounds 139 were synthesized in a similar manner using4-(difluoromethoxy)phenyl boronic acid and the appropriately substitutedamine variant of 123.

Compound 139. 11 mg, 9%, a gray solid.

Example 15. Synthesis of Compound 135

Synthesis of 135-A. To a solution of 123-E (300 mg, 1.35 mmol) inpyridine (6 mL) was added POCl₃ (1.04 g, 6.75 mmol) dropwise under icebath. The mixture was warmed to room temperature and stirred 1 h. Afterthe reaction was completed according to LCMS, the mixture was pouredinto ice water (10 mL). The precipitate was collected by filtration anddried to give 135-A (200 mg, 44%) as a yellow solid.

Synthesis of 135. A mixture of 242-5 (200 mg, 0.6 mmol) and Pd/C (50 mg)in EtOAc (10 mL) was stirred at room temperature for 2 h under H₂atmosphere. Pd/C was removed by filtration through Celite. The filtratewas concentrated in vacuo and the residue was purified by Pre-HPLC togive 135 (70 mg, 38%) as a white solid.

Compounds 126 and 141 were synthesized in a similar manner usingphenylboronic acid and the appropriately substituted acid variant of135.

Compound 126. 54 mg, 45%, a white solid.

Compound 141. 47 mg, 17%, a yellow solid.

Example 16. Synthesis of Compound 138

Synthesis of 138-A. To a solution of methoxymethyltriphenylphosphoniumchloride (1.03 g, 3.0 mmol) in THF (15 mL) was added potassiumhexamethyldisilane (1.8 mL, 1.7 M in toluene) dropwise at 0° C. Theresulting mixture was stirred at 50° C. for 2 h. Then a solution of143-D (576 mg, 1.50 mmol) in THF (5 mL) was added into above mixturedropwise. The mixture was stirred at 50° C. for 24 h. When the mixturewas cooled to room temperature. The mixture was diluted with water (15mL) and extracted with EtOAc (10 mL×3). The combined organic layer waswashed with brine (10 mL×3), dried over anhydrous Na₂SO₄ and thenconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (DCM:MeOH=50:1˜20:1) to give 138-A (200 mg, 32%) as ayellow solid.

Synthesis of 138-B. To a solution of 138-A (200 mg, 0.49 mmol) in THF (4mL) was added 1 N HCl (2.5 mL) dropwise. Then the solution was stirredat room temperature for 16 h. The solution was concentrated in vacuo togive 138-B as a crude product used to next step directly.

Synthesis of 138-C. To a mixture of 138-B (crude product from last step)and pyrrolidine (105 mg, 1.47 mmol) in DCE (5 mL) was added acetic acid(1 drop) and stirred at 50° C. for 1 h, then NaBH(OAc)₃ (312 mg, 1.47mmol) was added into above mixture. Then the mixture was stirred at 50°C. for 2 h. When the mixture was cooled to room temperature. The mixturewas diluted with water (15 mL) and extracted with DCM (10 mL×3). Thecombined organic layer was washed with brine (10 mL×3), dried overanhydrous Na₂SO₄ and then concentrated in vacuo. The residue waspurified by column chromatography on silica gel (DCM:MeOH=50:1˜10:1) togive 138-C (50 mg, 23% (two steps)) as a yellow solid.

Synthesis of 138. A mixture of 138-C (50 mg, 0.11 mmol) and Pd/C (50 mg)in MeOH (4 mL) was stirred at room temperature for 30 min under H₂atmosphere. Pd/C was removed by filtration through Celite. The filtratewas concentrated in vacuo and the residue was purified by Pre-TLC(DCM:MeOH=8:1) to give 138 (15 mg, 32%) as a light yellow solid.

Example 17. Synthesis of Compound 146

Synthesis of 146-A. A mixture of 1-(bromomethyl)-4-iodobenzene (2.50 g,8.4 mmol), dimethylamine hydrochloride (1.37 g, 16.8 mmol) and K₂CO₃(1.60 g, 33.6 mmol) in THF (50 mL) was stirred at room temperature for12 h. The mixture was diluted with DCM (100 mL) and washed with brine(40 mL×3). The combined organics washed with brine (30 mL×3), dried overanhydrous Na₂SO₄ and then concentrated in vacuo. The residue waspurified by column chromatography on silica gel (PE:EtOAc=5: 1-2:1) togive 146-A (1.70 g, 77%) as a yellow oil.

Synthesis of 146-B. To a mixture of Zn (628 mg, 9.6 mmol) in THF (3 mL)was added 1,2-dibromoethane (181 mg, 0.96 mmol) at room temperatureunder N₂. The mixture was heated to 65° C. and stirred for 10 min. Aftercooling to room temperature, TMSCl (104 mg, 0.96 mmol) was addeddropwise. The mixture was stirred for 30 min at room temperature, Znpowder turned dark and stickly. A solution of tert-butyl3-iodoazetidine-1-carboxylate (1.70 g, 6.0 mmol) in THF (3 mL) was addeddropwise during 1 h, but no obvious Zn powder consumption was observed.The mixture was heated to 65° C. for 10 min and the mixture turn hazy.After cooling to 25° C., the mixture was stirred for 1 h. The major Znwas consumed to give 146-B (used directly in the next step).

Synthesis of 146-C. To a solution of 146-B was added Pd₂(dba)₃ (34.5 mg,0.06 mmol) and tri-2-furylphosphine (56 mg, 0.24 mmol), followed by146-A (943 mg, 3.6 mmol) in THF (3 mL). The mixture was stirred at 65°C. for 16 h and then concentrated in vacuo. The residue was dissolvedwith DCM (50 mL) and the solution was washed with brine (20 mL×3). Theorganic layer was dried over anhydrous Na₂SO₄ and then concentrated invacuo. The residue was purified by column chromatography on silica gel(DCM:MeOH=100: 1-20:1) to give 146-C (200 mg, 20%) as a yellow solid.

Synthesis of 146-D. To a solution of 146-C (200 mg, 0.69 mmol) in DCM (5mL) was added TFA (2 mL) and stirred at room temperature for 1 h. whenLCMS showed the reaction was finished. The solvent was removed in vacuoto give 146-D as a crude product and used to next step directly.

Synthesis of 146-E. A mixture of 143-C (160 mg, 0.35 mmol) and 146-E(crude product from last step) in acetonitrile (5 mL) was stirred at 50°C. for 30 min. Then Na₂CO₃ (370 mg, 2.5 mmol) was added into abovemixture and stirred at 50° C. for 3 h. After the reaction was completedaccording to LCMS, the mixture was cooled to room temperature. TheNa₂CO₃ was removed by filtered. The filtrate was concentrated in vacuo.The residue was purified by column chromatography on silica gel(DCM:MeOH=100: 1-50:1) to give 146-E (50 mg, 35%) as a yellow solid.

Synthesis of 146. A mixture of 146-E (50 mg, 0.11 mmol) and Ni (50 mg)in MeOH (5 mL) was stirred at room temperature for 1 h under H₂atmosphere. Ni was then removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified by Pre-TLC togive 146 (12 mg, 26%) as a yellow solid.

Synthesis of 170. A mixture of 146-E (40 mg, 0.09 mmol) and Pd/C (40 mg)in MeOH (5 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified by Pre-TLC(DCM:MeOH=10:1) to give 170 (12 mg, 48%) as a yellow solid.

Example 18. Synthesis of Compound 147

Synthesis of 147-A. A solution of6-chloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine (2.00 g, 12.98 mmol) anddi-tert-butyl dicarbonate (4.24 g, 19.48 mmol) in DCM (40 mL) was addedDIEA (3.34 g, 25.96 mmol) dropwise. The mixture was stirred at roomtemperature for 1 h. After the reaction was completed according to TLC.The mixture was diluted with DCM (20 mL) and washed with brine (20mL×3). The combined organics washed with brine (20 mL×3), dried overanhydrous Na₂SO₄ and then concentrated in vacuo. The residue waspurified by column chromatography on silica gel (PE:EtOAc=2:1) to give147-A (2.10 g, 66%) as a white solid.

Synthesis of 147-B. A mixture of 147-A (600 mg, 2.4 mmol), azetidinehydrochloride (659 mg, 7.08 mmol), t-BuONa (680 mg, 7.08 mmol),Pd₂(dba)₃ (216 mg, 0.24 mmol) and XPhos (225 mg, 0.47 mmol) in toluene(12 mL) was stirred at 80° C. for 12 h under Ar atmosphere. The mixturewas diluted with EtOAc (30 mL) was added and the solution was washedwith brine (40 mL×3). The organic layer was dried over anhydrous Na₂SO₄and then concentrated in vacuo. The residue was purified by columnchromatography on silica gel (DCM:MeOH=50: 1-10:1) to give 147-B (500mg, 77%) as a yellow solid

Synthesis of 147-C. A solution of 147-B (250 mg, 0.91 mmol) in DCM (5mL) was added TFA (2 mL) and stirred at room temperature for 1 h. whenLCMS showed the reaction was finished. The solvent was removed in vacuoto give 147-C as a crude product (used in the next step directly).

Synthesis of 147-D. A mixture of 143-C (150 mg, 0.34 mmol) and 147-C(crude product from last step) in acetonitrile (5 mL) was stirred at 50°C. for 30 min. Then Na₂CO₃ (230 mg, 2.40 mmol) was added into abovemixture and stirred at 50° C. for 3 h. After the reaction was completedaccording to LCMS, the mixture was cooled to room temperature. TheNa₂CO₃ was removed by filtered. The filtrate was concentrated in vacuo.The residue was purified by column chromatography on silica gel(DCM:MeOH=100: 1-50:1) to give 147-D (80 mg, 58%) as a yellow solid.

Synthesis of 147. A mixture of 147-D (80 mg, 0.18 mmol) and Pd/C (80 mg)in MeOH (3 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by filtration through the celite. Thefiltrate was concentrated and the residue was purified by pre-TLC(DCM:MeOH=15:1) to give 147 (30 mg, 41%) as a yellow solid

Compounds 150, 157, 158, 159, 160, 254, 260 were synthesized in asimilar manner using the appropriately substituted amine a variant of147.

Compound 150. 50 mg, 67%, a yellow solid.

Compound 157. 15 mg, 16%, a yellow solid.

Compound 158. 12 mg, 13%, a yellow solid.

Compound 159. 80 mg, 57%, a yellow solid.

Compound 160. 60 mg, 43%, a yellow solid.

Compound 249. 20 mg, 25%, a white solid.

Compound 254. 53 mg, 57%, a yellow solid.

Example 19. Synthesis of Compound 148

Synthesis of 148-A. To a mixture of 147-A (600 mg, 2.36 mmol), SM-B (825mg, 3.54 mmol) and K₂CO₃ (980 mg, 7.08 mmol) in dioxane/H₂O (15 mL/1.5mL) was added Pd(PPh₃)₄ (96 mg, 0.12 mmol) under N₂ atmosphere. Themixture was stirred at 95° C. for 5 h and then concentrated in vacuo.The residue was dissolved with EtOAc (20 mL) and the solution was washedwith brine (20 mL×3). The organic layer was dried over anhydrous Na₂SO₄and then concentrated in vacuo. The residue was purified by columnchromatography on silica gel (PE:EtOAc=5:1˜2:1) to give 148-A (285 mg,40%) as a yellow solid.

Synthesis of 148-B. A solution of 148-A (280 mg, 0.88 mmol) in DCM (5mL) was added TFA (2 mL) and stirred at room temperature for 1 h. whenLCMS showed the reaction was finished. The solvent was removed in vacuoto give 148-B as a crude product (used in the next step directly).

Synthesis of 148-C. A mixture of 143-C (208 mg, 0.44 mmol) and 148-A(crude product from last step) in acetonitrile (5 mL) was stirred at 50°C. for 30 min. Then Na₂CO₃ (140 mg, 1.32 mmol) was added into abovemixture and stirred at 50° C. for 3 h. After the reaction was completedaccording to LCMS, the mixture was cooled to room temperature. TheNa₂CO₃ was removed by filtered. The filtrate was concentrated in vacuo.The residue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜50:1) to give 148-C (160 mg, 38%) as a yellow solid.

Synthesis of 148. A mixture of 1422-4 (80 mg, 0.16 mmol) and Pd/C (80mg) in MeOH (5 mL) was stirred at room temperature for 30 min under H₂atmosphere. Pd/C was then removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified by Pre-TLC(DCM:MeOH=15:1) to give 148 (30 mg, 40%) as a white solid.

Compounds 149, 240, 250, 251, 252, 253 and 255 were synthesized in asimilar manner using the appropriately substituted amine variant of 148.

Compound 149. 30 mg, 40%, a white solid.

Compound 240. 14 mg, 29%, a white solid.

Compound 250. 28 mg, 29%, a yellow solid.

Compound 251. 43 mg, 31%, a yellow solid.

Compound 252. 130 mg, 76%, a yellow solid.

Compound 253. 40 mg, 43%, as a yellow solid.

Compound 255. 10 mg, 32%, a white solid.

Example 20. Synthesis of Compound 151

Synthesis of 151-A. To a mixture of 147-A (320 mg, 1.38 mmol),trimethylboroxine (522 mg, 4.14 mmol) and K₂CO₃ (952 mg, 6.9 mmol) indioxane (15 mL) was added Pd(dppf)₂Cl₂ (57 mg, 0.07 mmol) under N₂atmosphere. The mixture was stirred at 95° C. for 24 h and thenconcentrated in vacuo. The residue was dissolved with EtOAc (20 mL) andthe solution was washed with brine (20 mL×3). The organic layer wasdried over anhydrous Na₂SO₄ and then concentrated in vacuo. The residuewas purified by column chromatography on silica gel (PE:EtOAc=5:1˜2:1)to give 151-A (160 mg, 50%) as a white solid.

Synthesis of 151-B. A solution of 151-A (160 mg, 0.68 mmol) in DCM (5mL) was added TFA (2 mL) and stirred at room temperature for 1 h. whenLCMS showed the reaction was finished. The solvent was removed in vacuoto give 151-B as a crude product used in the next step directly.

Synthesis of 151-C. A mixture of 143-C (215 mg, 0.45 mmol) and 151-B(crude product from last step) in DMSO (5 mL) was stirred at roomtemperature for 10 min. Then Na₂CO₃ (382 mg, 3.6 mmol) was added intoabove mixture and stirred at room temperature for 2 h. After thereaction was completed according to LCMS, the mixture was diluted withwater (30 mL) and extracted with EtOAc (10 mL×3). The combined organiclayer was washed with brine (10 mL×3), dried over anhydrous Na₂SO₄ andthen concentrated in vacuo. The residue was purified by columnchromatography on silica gel (DCM:MeOH=100:1˜50:1) 151-C (160 mg, 90%)as a yellow solid.

Synthesis of 151. A mixture of 151-C (160 mg, 0.41 mmol) and Pd/C (160mg) in MeOH (5 mL) was stirred at room temperature for 30 min under H₂atmosphere. Pd/C was then removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified by Pre-TLC(DCM:MeOH=10:1) to give 151 (103 mg, 69%) as a white solid.

Example 21. Synthesis of Compound 153

Synthesis of 153-A. To a mixture of 4-chloropyridin-3-amine (30.0 g,234.4 mmol) and TEA (47.3 g, 468.8 mmol) in THF (600 mL) was addedmethyl 2-chloro-2-oxoacetate (30.0 g, 246.2 mmol) dropwise at ice bath.The solution was stirred at room temperature for 2 h. The reactionmixture was diluted with water (100 mL) and then extracted with EtOAc(100 mL×3). The combined organics washed with brine (100 mL×3), driedover anhydrous Na₂SO₄ and then concentrated in vacuo. The residue waspurified by column chromatography on silica gel (PE:EtOAc=10:1˜5:1) togive 153-A (31.0 g, 62%) as a white solid.

Synthesis of 153-B. A mixture of 153-A (15.0 g, 70.1 mmol) andLawesson's reagent (19.8 g, 49.1 mmol) in toluene (300 mL) was heated toreflux overnight. The reaction mixture was diluted with water (100 mL)and then extracted with EtOAc (100 mL×3). The combined organics washedwith brine (100 mL×3), dried over anhydrous Na₂SO₄ and then concentratedin vacuo. The residue was purified by column chromatography on silicagel (PE:EtOAc=10:1˜3:1) to give 153-B (2.0 g, 15%) as a yellow solid.

Synthesis of 153-C. A mixture of 153-B (2.0 g, 10.3 mmol) and PtO₂ (400mg) in acetic acid (100 mL) was stirred at 70° C. overnight under H₂atmosphere at 5 MPa. PtO₂ was then removed by filtration through theCelite. The filtrate was concentrated and the residue was purified bycolumn chromatography on silica gel (DCM:MeOH=50:1˜20:1) to give 153-C(820 mg, 40%) as a white solid.

Synthesis of 153-D. A mixture of 153-C (360 mg, 1.82 mmol) andformaldehyde solution (37% w/w, 0.7 mL) and acetic acid (2 drops) inMeOH (10 mL) was stirred at 40° C. for 1 h, then NaBH(OAc)₃ (772 mg,3.64 mmol) was added into above solution. The reaction mixture wasstirred at 40° C. for 2 h. The solution was cooled to room temperature.The solution was diluted with water (10 mL), extracted with EtOAc (10mL×3). The combined organic layer was washed with brine (10 mL×3), driedover anhydrous Na₂SO₄ and then concentrated in vacuo. The residue waspurified by column chromatography on silica gel (DCM:MeOH=50:1˜20:1) togive 153-D (350 mg, 91%) as a white solid.

Synthesis of 153-E. A mixture of 153-D (350 mg, 1.65 mmol) and LiOH.H₂O(139 mg, 3.30 mmol) in MeOH/H₂O (10 mL/4 mL) was stirred at roomtemperature overnight. After the reaction was completed according toLCMS, MeOH was removed in vacuo. The aqueous was adjusted to pH=6 with1N HCl. Then the solution was concentrated to dryness to give 196-D as awhite solid, which was used directly to next step without furtherpurification.

Synthesis of 154-F. To a solution of CDI (161 mg, 0.99 mmol) in DMF (5mL) was added 154-E (0.83 mmol, crude product from last step) inportions and the solution was stirred at room temperature for 1 h togive solution A. At the same time, to a solution of 143-B (193 mg, 0.83mmol) in DMF (5 mL) was added NaH (60% in mineral oil) (66 mg, 1.65mmol) in portions and the mixture was stirred at room temperature for 1h to give solution B. Then, the solution A was added into the solution Bdropwise and the resulting mixture continue to stir at room temperaturefor 1 h. After the reaction was completed according to LCMS, the mixturewas poured into water (10 mL). The precipitate was collected by filteredand concentrated to dryness to give 154-F (150 mg, 44%) as a yellowsolid.

Synthesis of 153. A mixture of 169-C (150 mg, 0.36 mmol) and Pd/C (150mg) in EtOAc (5 mL) was stirred at room temperature for 30 min under H₂atmosphere. Pd/C was then removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified by Pre-TLC(DCM:MeOH=8:1) to give 153 (100 mg, 70%) as a white solid.

Compound 165 was synthesized in a similar manner using the appropriatelysubstituted halogen variant of 153.

Compound 165. 80 mg, 57%, a yellow solid.

Compound 163 was synthesized in a similar manner using furan-2-ylboronicacid and the appropriately substituted halogen variant of 153.

Compound 163. 35 mg, 38%, a white solid.

Compound 164 was synthesized in a similar manner usingpyridin-3-ylboronic acid and the appropriately substituted halogenvariant of 153.

Compound 164. 10 mg, 14%, a yellow solid.

Example 22. Synthesis of Compound 155

Synthesis of 155-A. A mixture of potassium (bromomethyl)trifluoroborate(1.00 g, 4.98 mmol) and pyrrolidine (371 mg, 5.23 mmol) in THF (10 mL)was stirred at 80° C. for 4 h. The solvent was removed in vacuo. Theresidue was dissolved in acetone and the solution filtered to removeKCl. The filtrate was concentrated in vacuo, dissolved in a minimalamount of hot acetone (10 mL), and precipitated by the dropwise additionof Et₂O (5 mL). Additional Et₂O (150 mL) was added to facilitatefiltering to give 155-A (750 mg, 98%) as a white solid.

Synthesis of 155-B. A mixture of 155-A (750 mg, 4.90 mmol), SM-A (500mg, 4.67 mmol), Cs₂CO₃ (4.56 g, 14.0 mmol), Pd(OAc)₂ (52 mg, 0.23 mmol)and XPhos (224 mg, 0.47 mmol) in THF/H₂O (20 mL/2 mL) was stirred 80° C.for 12 h under Ar. The mixture was cooled to room temperature anddiluted with H₂O (50 mL). The mixture was extracted with EtOAc (20mL×3). The combined organics washed with brine (20 mL×3), dried overanhydrous Na₂SO₄ and then concentrated in vacuo. The residue waspurified by column chromatography on silica gel (PE:EtOAc=8:1˜3:1) togive 155-B (700 mg, 47%) as a yellow solid.

Synthesis of 155-C. To a solution of 155-B (350 mg, 1.15 mmol) in DCM (8mL) was added TFA (4 mL) and stirred at room temperature for 1 h. whenLCMS showed the reaction was finished. The solvent was removed in vacuoto give 155-C as a crude product and used to next step directly.

Synthesis of 155-D. A mixture of 143-C (200 mg, 0.42 mmol) and 155-C(crude product from last step) in acetonitrile (5 mL) was stirred at 50°C. for 30 min. Then Na₂CO₃ (356 mg, 3.36 mmol) was added into abovemixture and stirred at 50° C. for 3 h. After the reaction was completedaccording to LCMS, the mixture was cooled to room temperature. TheNa₂CO₃ was removed by filtered. The filtrate was concentrated in vacuo.The residue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜50:1) to give 155-D (180 mg, 93%) as a yellow solid.

Synthesis of 155. A mixture of 155-D (180 mg, 0.39 mmol) and Pd/C (180mg) in MeOH (5 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified by Pre-TLC(DCM:MeOH=8:1) to give 155 (125 mg, 74%) as a yellow solid

Compound 144 was synthesized in a similar manner usingthiophen-2-ylboronic acid variant of 155. Compound 144. 80 mg, 60%, ayellow solid.

Example 23. Synthesis of Compound 156

Synthesis of 156-A. A mixture of 6-chloro-3-nitropyridin-2-amine (10.00g, 57.6 mmol), thiophen-2-ylboronic acid (8.12 g, 63.4 mmol) and Cs₂CO₃(37.56 g, 115.2 mmol) in dioxane/H₂O (200 mL/20 mL) was added Pd(PPh₃)₄(2.44 g, 2.88 mmol) under N₂ atmosphere. The mixture was stirred at 95°C. for 2 h and then concentrated in vacuo. The residue was dissolvedwith EtOAc (200 mL) and the solution was washed with brine (100 mL×3).The organic layer was dried over anhydrous Na₂SO₄ and then concentratedin vacuo. The residue was purified by column chromatography on silicagel (PE:EtOAc=5:1˜3:1) to give 156-A (10.0 g, 79%) as a yellow solid

Synthesis of 156-B. A stirred solution of 156-A (1.30 g, 5.88 mmol) inpyridine (20 mL) was added phenyl carbonochloridate (2.29 g, 14.7 mmol)dropwise. After the addition was completed, the mixture was heated to50° C. for 4 h. The mixture was concentrated in vacuo. The residue waspurified by column chromatography on silica gel (PE:EtOAc=8:1˜3:1) togive 156-B (2.4 g, 89%) as a yellow solid

Synthesis of 156-C. A mixture of 156-B (300 mg, 0.65 mmol) and 143-C(190 mg, 0.98 mmol) in DMSO (10 mL) was stirred at room temperature for10 min, then Na₂CO₃ (312 mg, 3.25 mmol) was added into above mixture andstirred at room temperature for 2 h. The mixture was diluted with water(30 mL) and extracted with EtOAc (10 mL×3). The combined organic layerwas washed with brine (10 mL×3), dried over anhydrous Na₂SO₄ and thenconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (DCM:MeOH=100:1˜20:1) to give 156-C (200 mg, 84%) as ayellow solid.

Synthesis of 143. A mixture of 143-E (200 mg, 0.54 mmol) and Pd/C (200mg) in MeOH (5 mL) was stirred at room temperature for 30 min under H₂atmosphere. Pd/C was removed by filtration through Celite. The filtratewas concentrated in vacuo and the residue was purified by Pre-TLC(DCM:MeOH=10:1) to give 156 (118 mg, 65%) as a light yellow solid.

Compounds 173 and 187 were synthesized in a similar manner using4-methoxyphenylboronic acid the appropriately substituted amine variantof 156.

Compound 173. 6 mg, 7%, a yellow solid.

Compound 187. 85 mg, 71%, a yellow solid.

Compounds 186, 224, 229, 238, 259 and 260 were synthesized in a similarmanner using 4-fluorophenylboronic acid the appropriately substitutedamine variant of 156.

Compound 186. 35 mg, 37%, a white solid.

Compound 224. 40 mg, 26%, a yellow solid.

Compound 225. 25 mg, 13%, a white solid.

Compound 229. 12 mg, 43%, a white solid.

Compound 238. 70 mg, 50%, a yellow solid

Compound 259. 20 mg, 20%, a red solid.

Compound 260. 50 mg, 54%, a yellow solid.

Compounds 197 and 212 were synthesized in a similar manner usingphenylboronic acid the appropriately substituted amine variant of 156.

Compound 197. 16 mg, 43%, a yellow solid.

Compound 212. 80 mg, 87%, a white solid.

Compounds 214, 216, 218 and 221 were synthesized in a similar mannerusing pyridin-3-ylboronic acid and the appropriately substituted aminevariant of 156.

Compound 171. 15 mg, 25%, a yellow solid.

Compound 214. 7 mg, 10%, a yellow solid.

Compound 216. 30 mg, 41%, a yellow solid.

Compound 217. 25 mg, 22%, a yellow solid.

Compound 218. 30 mg, 33%, a yellow solid.

Compound 220. 20 mg, 16%, a yellow solid.

Compound 221. 165 mg, 66%, a white solid.

Compounds 228, 230 and 232 were synthesized in a similar manner using4-(difluoromethoxy)phenylboronic acid and the appropriately substitutedamine variant of 156.

Compound 228. 25 mg, 21%, a yellow solid.

Compound 230. 20 mg, 71%, a white solid.

Compound 232. 70 mg, 51%, a white solid.

Compound 231 was synthesized in a similar manner using1-methyl-1H-pyrazol-4-ylboronic acid and the appropriately substitutedamine variant of 156.

Compound 231. 35 mg, 28%, a yellow solid.

Example 24. Synthesis of Compound 167

Synthesis of 167-A. A mixture of 6-chloro-3-nitropyridin-2-amine (6.00g, 34.6 mmol), 1H-pyrazole (7.06 g, 103.76 mmol) and t-BuOK (11.64 g,103.76 mmol) in dioxane (120 mL) was stirred at 120° C. under microwavefor 1 h. The mixture was diluted with water (50 mL) and extracted withEtOAc (50 mL×3). The combined organic layer was washed with brine (10mL×3), dried over anhydrous Na₂SO₄ and then concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(PE:EtOAc=2:1˜1:2) to give 167-A (4.0 g, 56%) as a yellow solid

Synthesis of 167-B. A stirred solution of 167-A (2.00 g, 9.75 mmol) inpyridine (40 mL) was added phenyl carbonochloridate (3.36 g, 21.44 mmol)dropwise. After the addition was completed, the mixture was hated to 50°C. for 2 h. The mixture was concentrated in vacuo. The residue waspurified by column chromatography on silica gel (PE:EtOAc=5:1˜2:1) togive 167-C (3.2 g, 74%) as a yellow solid.

Synthesis of 167-D. A mixture of 167-C (258 mg, 0.58 mmol), 183-B (183mg, 1.16 mmol) and Na₂CO₃ (286 mg, 2.31 mmol) in acetonitrile wasstirred at 50° C. for 3 h. The mixture was cooled to room temperature.The Na₂CO₃ was removed by filtered. The filtrate was concentrated invacuo. The residue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜50:1) to give 167-D (160 mg, 71%) as a yellow solid.

Synthesis of 167. A mixture of 167-D (160 mg, 0.41 mmol) and Pd/C (160mg) in MeOH (5 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified by pre-TLC(DCM:MeOH=8:1) to give 167 (125 mg, 84%) as a white solid.

Compounds 177, 184, 185 and 190 were synthesized in a similar mannerusing the appropriately substituted amine variant of 176.

Compound 177. 75 mg, 65%, a yellow solid.

Compound 184. 20 mg, 11%, a yellow solid.

Compound 185. 30 mg, 33%, a white solid.

Compound 190. 20 mg, 36%, a yellow solid.

Example 25. Synthesis of Compound 168

Synthesis of 168-A. A mixture of potassium (bromomethyl)trifluoroborate(1.00 g, 4.98 mmol) and 1-methylpiperazine (524 mg, 5.23 mmol) in THF(10 mL) was stirred at 80° C. for 4 h. The solvent was removed in vacuo.The residue was dissolved in acetone and the solution filtered to removeKCl. The filtrate was concentrated in vacuo, dissolved in a minimalamount of hot acetone (10 mL), and precipitated by the dropwise additionof Et₂O (5 mL). Additional Et₂O (150 mL) was added to facilitatefiltering to give 168-A (760 mg, 79%) as a white solid.

Synthesis of 168-B. A mixture of 168-A (336 mg, 1.80 mmol), SM-A (500mg, 1.70 mmol), Cs₂CO₃ (1.60 g, 5.0 mmol), Pd(OAc)₂ (12 mg, 0.05 mmol)and XPhos (48 mg, 0.1 mmol) in THF/H₂O (10 mL/1 mL) was stirred 80° C.for 12 h under Ar. The mixture was cooled to room temperature anddiluted with H₂O (50 mL). The mixture was extracted with DCM (20 mL×3).The combined organics washed with brine (20 mL×3), dried over anhydrousNa₂SO₄ and then concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (PE:EtOAc=8:1˜3:1) to give 168-B(320 mg, 60%) as a yellow solid.

Synthesis of 168-C. To a solution of 168-B (200 mg, 0.62 mmol) in DCM (4mL) was added TFA (2 mL) and stirred at room temperature for 1 h. whenLCMS showed the reaction was finished. The solvent was removed in vacuoto give 168-C as a crude product and used to next step directly.

Synthesis of 168-D. A mixture of 143-C (160 mg, 0.35 mmol) and 168-C(crude product from last step) in acetonitrile (5 mL) was stirred at 50°C. for 30 min. Then Na₂CO₃ (370 mg, 2.5 mmol) was added into abovemixture and stirred at 50° C. for 3 h. After the reaction was completedaccording to LCMS, the mixture was cooled to room temperature. TheNa₂CO₃ was removed by filtered. The filtrate was concentrated in vacuo.The residue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜50:1) to give 168-D (130 mg, 75%) as a yellow solid.

Synthesis of 168. A mixture of 168-D (130 mg, 0.26 mmol) and Pd/C (130mg) in MeOH (5 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified by Pre-TLC(DCM:MeOH=8:1) to give 168 (100 mg, 83%) as a yellow solid

Compounds 154, 155, 162 and 178 were synthesized in a similar mannerusing the appropriately substituted amine variant of 168.

Compound 154. 60 mg, 64%, a yellow solid

Compound 155. 110 mg, 65%, a yellow solid

Compound 162. 18 mg, 50%, a yellow solid

Compound 178. 125 mg, 61%, a white solid.

Compounds 144 and 145 were synthesized in a similar manner usingthiophen-2-ylboronic acid and the appropriately substituted aminevariant of 168.

Compound 144. 80 mg, 60%, a yellow solid

Compound 145. 50 mg, 15%, a yellow solid

Compound 161 was synthesized in a similar manner usingpyridin-3-ylboronic acid and the appropriately substituted amine variantof 168.

Compound 161. 30 mg, 32%, a yellow solid.

Compound 261 was synthesized in a similar manner using4-fluoro-2-methylphenylboronic acid and the appropriately substitutedamine variant of 168.

Compound 261. 46 mg, 55%, a yellow solid

Example 26. Synthesis of Compound 169

Synthesis of 169-A. A mixture of tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (750 mg, 3.54 mmol),1-methylpiperidin-4-one (800 mg, 7.08 mmol) and acetic acid (2 drops) inDCE (15 mL) was stirred at 50° C. for 2 h. Then Sodiumtriacetoxyborohydride (1.50 g, 7.08 mmol) was added into above mixtureand stirred at 50° C. for another 2 h. After the reaction was completedaccording to LCMS, the solvent was diluted with water (10 mL) and thenextracted by DCM (10 mL×3). The combined organics washed with brine (10mL×3), dried over anhydrous Na₂SO₄ and then concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜50:1) to give 169-A (750 mg, 69%) as a yellow oil.

Synthesis of 169-B. A solution of 169-A (400 mg, 1.29 mmol) in DCM (10mL) was added TFA (5 mL) and stirred at room temperature for 1 h. whenLCMS showed the reaction was finished. The solvent was removed in vacuoto give 169-B as a crude product and used to next step directly.

Synthesis of 169-C. A mixture of 143-C (306 mg, 0.65 mmol) and 169-B(crude product from last step) in acetonitrile (6 mL) was stirred at 50°C. for 30 min. Then Na₂CO₃ (624 mg, 6.50 mmol) was added into abovemixture and stirred at 50° C. for 3 h. After the reaction was completedaccording to LCMS, the mixture was cooled to room temperature. TheNa₂CO₃ was removed by filtered. The filtrate was concentrated in vacuo.The residue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜20:1) to give 169-C (230 mg, 76%) as a yellow solid.

Synthesis of 169. A mixture of 169-C (230 mg, 0.49 mmol) and Pd/C (230mg) in MeOH (10 mL) was stirred at room temperature for 30 min under H₂atmosphere. Pd/C was then removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified by Pre-TLC(DCM:MeOH=10:1) to give 169 (150 mg, 70%) as a white solid.

Compounds 152, 182, 199, 201, 202, 203, 235, 236 and 256 weresynthesized in a similar manner using the appropriately substitutedaldehyde or ketone variant of 169.

Compound 152. 50 mg, 36%, a light yellow solid.

Compound 182. 70 mg, 38%, a red solid.

Compound 199. 50 mg, 54%, a light yellow solid.

Compound 201. 30 mg, 42%, as a yellow solid.

Compound 202. 30 mg, 42%, a yellow solid.

Compound 203. 30 mg, 18%, a yellow solid.

Compound 235. 170 mg, 87%, a white solid.

Compound 236. 70 mg, 50%, a white solid.

Compound 256. 20 mg, 8%, a light yellow solid.

Compounds 210, 211, 215, 222, 223, 242 and 262 were synthesized in asimilar manner using the appropriately substituted amine variant of 169.

Compound 210. 160 mg, 96%, a tan solid.

Compound 211. 70 mg, 40%, a white solid

Compound 215. 70 mg, 75%, a white solid.

Compound 222. 30 mg, 42%, a yellow solid.

Compound 223. 35 mg, 31%, a white solid.

Compound 242. 50 mg, 34%, a white solid.

Compound 262. 38 mg, 43%, a white solid.

Example 27. Synthesis of Compound 183

Synthesis of 183-A. A solution of tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.00 g, 9.4 mmol),1-bromo-2-fluoroethane (2.35 g, 18.8 mmol) and TEA (1.90 g, 18.8 mmol)in DCM (40 mL) was stirred at room temperature for 24 h. The mixture wasdiluted with DCM (40 mL) and washed with brine (20 mL×3), dried overanhydrous Na₂SO₄ and then concentrated in vacuo. The residue waspurified by column chromatography on silica gel (PE:EtOAc=20:1˜5:1) togive 183-A (1.50 g, 63%) as a colorless oil.

Synthesis of 183-B. A solution of 183-A (200 mg, 0.77 mmol) in DCM (5mL) was added TFA (2 mL) and stirred at room temperature for 1 h. whenLCMS showed the reaction was finished. The solvent was removed in vacuoto give 183-B as a crude product and used to next step directly.

Synthesis of 183-C. A mixture of 143-C (180 mg, 0.39 mmol), 183-B (0.77mmol, a crude product from last step) and K₂CO₃ (270 mg, 1.95 mmol) inacetonitrile was stirred at 50° C. for 3 h. The mixture was cooled toroom temperature. The Na₂CO₃ was removed by filtered. The filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (DCM:MeOH=100:1˜50:1) to give 183-C (130 mg, 85%) as ayellow solid.

Synthesis of 183. A mixture of 183-c (130 mg, 0.31 mmol) and Pd/C (130mg) in MeOH (10 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by filtration through the celite. Thefiltrate was concentrated and the residue was purified by pre-TLC(DCM:MeOH=10:1) to give 183 (90 mg, 75%) as a yellow solid

Compounds 166 and 176 were synthesized in a similar manner using theappropriately substituted amine variant of 183.

Compound 166. 12 mg, 28%, a white solid.

Compound 176. 35 mg, 41%, a white solid.

Compounds 174 and 175 were synthesized in a similar manner usingfuran-2-ylboronic acid and the appropriately substituted amine variantof 183

Compound 174. 65 mg, 50%, a yellow solid.

Compound 175. 20 mg, 11%, a yellow solid.

Example 28. Synthesis of Compound 192

Synthesis of 192-A. To a solution of azetidine-3-carboxylic acid (5.00g, 49.5 mmol) in MeOH (100 mL) was added SOCl₂ (11.8 g, 99.0 mmol)dropwise at ice bath. The solution was stirred at room temperatureovernight. The reaction mixture concentrated to dryness to give 192-A(6.8 g, 90%) as a white solid.

Synthesis of 192-B. A mixture of 2,3-dichloropyridine (5.0 g, 31.6mmol), 192-A (5.7 g, 37.9 mmol) and DIEA (12.2 g, 94.8 mmol) in DMSO(100 mL) was heated to 120° C. for 1 h. The reaction mixture was dilutedwith water (100 mL) and then extracted with EtOAc (100 mL×3). Thecombined organics washed with brine (100 mL×3), dried over anhydrousNa₂SO₄ and then concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (PE:EtOAc=10:1˜5:1) to give 192-B(1.0 g, 14%) as a yellow solid.

Synthesis of 192-C. A mixture of 192-B (1.0 g, 4.42 mmol), TEA (1.3 g,13.26 mmol) and Pd/C (1.0 g) in MeOH (40 mL) was stirred at 40° C. for 1h under H₂ atmosphere. Pd/C was then removed by filtration through theCelite. The filtrate was concentrated and the residue was dissolved withDCM (50 mL), washed with brine (20 mL×3), dried over anhydrous Na₂SO₄and then concentrated in vacuo to give 192-C (770 mg, 91%) as a yellowsolid.

Synthesis of 192-D. A mixture of 192-C (700 mg, 3.65 mmol) and LiOH.H₂O(460 mg, 10.95 mmol) in MeOH/H₂O (10 mL/10 mL) was stirred at roomtemperature for 2 h. After the reaction was completed according to LCMS,the MeOH was removed in vacuo. The aqueous was adjusted to pH=6 with 1NHCl. Then the solution was concentrated to dryness to give 192-D as awhite solid, which was used directly to next step without furtherpurification.

Synthesis of 192-E. To a solution of CDI (162 mg, 1.0 mmol) in DMF (5mL) was added 192-D (1.0 mmol, crude product from last step) in portionsand the solution was stirred at room temperature for 1 h to givesolution A. At the same time, to a solution of 143-B (233 mg, 1.0 mmol)in DMF (5 mL) was added NaH (60% in mineral oil) (120 mg, 3.0 mmol) inportions and the mixture was stirred at room temperature for 1 h to givesolution B. Then, the solution A was added into the solution B dropwiseand the resulting mixture continue to stir at room temperature for 1 h.After the reaction was completed according to LCMS, the mixture waspoured into water (10 mL). The precipitate was collected by filtered andconcentrated to dryness to give 192-E (160 mg, 41%) as a yellow solid.

Synthesis of 192. A mixture of 169-C (160 mg, 0.36 mmol) and Pd/C (160mg) in MeOH (5 mL) was stirred at room temperature for 30 min under H₂atmosphere. Pd/C was then removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified by Pre-TLC(DCM:MeOH=10:1) to give 192 (60 mg, 39%) as a white solid.

Compounds 193 and 195 were synthesized in a similar manner using theappropriately substituted amine variant of 192.

Compound 193. 80 mg, 41%, a white solid.

Compound 195. 60 mg, 43%, a gray solid.

Example 29. Synthesis of Compound 196

Synthesis of 196-A. To a mixture of tert-butyl piperazine-1-carboxylate(200 mg, 1.1 mmol) and TEA (326 mg, 3.3 mmol) in DCM (20 mL) was addedacetyl chloride (93 mg, 1.2 mmol) dropwise at ice bath. The reactionmixture was stirred at room temperature for 3 h. After the reaction wascompleted according to LCMS, the solution was diluted with DCM (15 mL)and the resulting solution was washed with brine (10 mL×3). The organiclayer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜30:1) to give 196-A (150 mg, 60%) as a light yellowsolid.

Synthesis of 196-B. A solution of 196-A (150 mg, 0.66 mmol) inHCl/dioxane (2 N, 5 mL) was stirred at room temperature for 2 h. Afterthe reaction was completed according to LCMS, the solution wasconcentrated to give 196-B as a crude product, used directly to nextstep without further purification.

Synthesis of 196-C. A solution of 196-B (0.66 mmol, crude product fromlast step), methyl 2-bromoacetate (100 mg, 0.66 mmol) and DIEA (428 mg,3.30 mmol) in MeCN (5 mL) stirred at room temperature for 3 h. After thereaction was completed according to LCMS, the mixture was diluted withwater (5 mL) and extracted with EtOAc (5 mL×3). The combined organicswashed with brine (50 mL×3), dried over anhydrous Na₂SO₄ and thenconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (DCM:MeOH=50:1˜10:1) to give 196-C (120 mg, 91%) as alight yellow oil.

Synthesis of 196-D. A solution of 196-C (120 mg, 0.60 mmol) and LiOH.H₂O(101 mg, 2.40 mmol) in MeOH/H₂O (10 mL/10 mL) was stirred at roomtemperature overnight. After the reaction was completed according toLCMS, the MeOH was removed in vacuo. The aqueous was adjusted to pH=6 by1N HCl. Then the solution was concentrated to dryness to give 196-D as acrude product, which was used directly to next step without furtherpurification.

Synthesis of 196-E. To a solution of CDI (97 mg, 0.60 mmol) in DMF (2mL) was added 196-D (0.60 mmol, crude product from last step) inportions and the solution was stirred at room temperature for 1 h togive solution A. At the same time, to a solution of3-nitro-6-phenylpyridin-2-amine (129 mg, 0.60 mmol) in DMF (4 mL) wasadded NaH (60% in mineral oil) (48 mg, 1.2 mmol) in portions and themixture was stirred at room temperature for 1 h to give solution B.Then, the solution A was added into the solution B in dropwise and theresulting mixture continue to stir at room temperature for 1 h. Afterthe reaction was completed according to LCMS, the mixture was pouredinto water (10 mL). The precipitate was collected by filtered andconcentrated to dryness to give 196-E (150 mg, 56%) as a yellow solid.

Synthesis of 196. A mixture of 196-E (150 mg, 0.39 mmol) and Pd/C (150mg) in EtOAc (10 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by the filtration through the Celite.The filtrate was concentrated and the residue was purified by Pre-TLC(DCM:MeOH=8:1) to give 196 (120 mg, 87%) as a white solid.

Compound 194 was synthesized in a similar manner using the appropriatelysubstituted acid variant of 196.

Compound 194. 16 mg, 43%, a yellow solid.

Example 30. Synthesis of Compound 198

Synthesis of 198-A. A mixture of 6-bromo-3-nitropyridin-2-amine (5.0 g,23.0 mmol), furan-2-ylboronic acid (3.1 g, 27.6 mmol) and Cs₂CO₃ (22.5g, 69.0 mmol) in dioxane/H₂O (100 mL/10 mL) was added Pd(PPh₃)₄ (2.44 g,2.88 mmol) under N₂ atmosphere. The mixture was stirred at 95° C. for 3h and then concentrated in vacuo. The residue was dissolved with EtOAc(200 mL) and the solution was washed with brine (100 mL×3). The organiclayer was dried over anhydrous Na₂SO₄ and then concentrated in vacuo.The residue was purified by column chromatography on silica gel(PE:EtOAc=10:1˜5:1) to give 198-A (2.0 g, 42%) as a yellow solid.

Synthesis of 198-B. To a solution of CDI (395 mg, 2.44 mmol) in DMF (5mL) was added 196-D (490 mg, 2.44 mmol) in portions and the solution wasstirred at room temperature for 1 h to give solution A. At the sametime, to a solution of 198-A (500 mg, 2.44 mmol) in DMF (5 mL) was addedNaH (60% in mineral oil) (195 mg, 4.88 mmol) in portions and the mixturewas stirred at room temperature for 1 h to give solution B. Then, thesolution A was added into the solution B in dropwise and the resultingmixture continue to stir at room temperature for 1 h. After the reactionwas completed according to LCMS, the solution was diluted with water (20mL), extracted with EtOAc (10 mL×5). The combined organic layer waswashed with brine (10 mL×3), dried over anhydrous Na₂SO₄ and thenconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (PE:EtOAc=10:1˜2:1) to give 198-B (680 mg, 72%) as ayellow solid.

Synthesis of 198-C. To a solution of 198-B (200 mg, 0.52 mmol) in DCM (5mL) was added TFA (2 mL) dropwise under ice bath. Then the solution wasstirred at room temperature 1 h. The solvent was removed in vacuo togive 198-C as a crude product.

Synthesis of 198-D. A mixture of 198-C (0.52 mmol, crude product fromlast step), benzaldehyde (110 mg, 1.04 mmol) and acetic acid (2 drops)in MeOH (5 mL) was stirred at 40° C. for 1 h, then NaBH(OAc)₃ (221 g,1.04 mmol) was added into above solution. The reaction mixture wasstirred at 40° C. for 4 h. The solution was cooled to room temperature.The solution was diluted with water (10 mL), extracted with EtOAc (10mL×3). The combined organic layer was washed with brine (10 mL×3), driedover anhydrous Na₂SO₄ and then concentrated in vacuo. The residue waspurified by column chromatography on silica gel (DCM:MeOH=200:1˜50:1) togive 198-D (110 mg, 56% (two step)) as a yellow solid.

Synthesis of 198. A mixture of 198-D (110 mg, 0.29 mmol), zinc powder(94 mg, 1.45 mmol) and ammonium formate (183 mg, 2.90 mmol) in MeOH (3mL) was stirred at room temperature for 1 h. The zinc powder was thenremoved by filtration through the Celite. The filtrate was concentratedand the residue was purified by Pre-TLC (DCM:MeOH=15:1) to give 198 (20mg, 20%) as a yellow solid.

Compound 204, 239, 241, 263 and 264 was synthesized in a similar mannerusing 4-fluorophenylboronic acid and the appropriately substituted acidvariant of 198.

Compound 204. 60 mg, 73%, a white solid.

Compound 239. 60 mg, 62%, a white solid.

Compound 241. 69 mg, 58%, a white solid.

Compound 263. 83 mg, 64%, a white solid.

Compound 264. 50 mg, 79%, a white solid.

Compound 205 was synthesized in a similar manner using 1H-pyrazole andthe appropriately substituted acid variant of 205.

Compound 205. 20 mg, 43%, a white solid.

Example 31. Synthesis of Compound 206

Synthesis of 206-A. A mixture of ethyl 3-bromo-2-oxopropanoate (10.8 g,55.3 mmol) and pyrazin-2-amine (5.0 g, 52.6 mmol) in DME (150 mL) wasstirred at room temperature for 5 h. The precipitate was collected byfiltered. Then the cake was dissolved in EtOH (100 mL) and stirred at80° C. for 2 h. The solvent was removed in vacuo. The residue waspurified by column chromatography on silica gel (PE:EtOAc=2:1˜1:2) togive 206-A (2.0 g, 20%) as a yellow solid.

Synthesis of 206-B. A mixture of 206-A (1.50 g, 7.85 mmol), Pd/C (750mg) and conc. HCl (15 mL) in EtOH (285 mL) was stirred at roomtemperature for 16 h under H₂ atmosphere at 40 psi. Pd/C was thenremoved by the filtration through the Celite. The filtrate wasconcentrated to give 206-B as a crude product, which was used directlyto next step without further purification.

Synthesis of 206-C. To a solution of 206-B (4.1 mmol, crude product fromlast step) and formaldehyde solution (37% w/w, 2 mL) and acetic acid (2drops) in MeOH (20 mL) was stirred at 40° C. for 1 h, then NaBH(OAc)₃(2.61 g, 12.3 mmol) was added into above solution. The reaction mixturewas stirred at 40° C. for 2 h. The solution was cooled to roomtemperature. The solution was diluted with water (10 mL), extracted withEtOAc (10 mL×3). The combined organic layer was washed with brine (10mL×3), dried over anhydrous Na₂SO₄ and then concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM:MeOH=100:1˜30:1) to give 206-C (500 mg, 58%) as a yellow solid.

Synthesis of 206-D. A solution of 196-C (500 mg, 2.4 mmol) and LiOH.H₂O(400 mg, 9.6 mmol) in MeOH/H₂O (10 mL/10 mL) was stirred at roomtemperature overnight. After the reaction was completed according toLCMS, the MeOH was removed in vacuo. The aqueous was adjusted to pH=6 by1N HCl. Then the solution was concentrated to dryness to give 206-D as acrude product, which was used directly to next step without furtherpurification.

Synthesis of 206-E. To a solution of 206-D (0.50 mmol, crude productfrom last step) and DMF (1 drop) in DCM (5 mL) was added (COCl)₂ (127mg, 1.0 mmol) at ice bath. The resulting mixture was stirred at roomtemperature for 1 h and concentrated to give a white solid A. At thesame time, to a solution of 3-nitro-6-phenylpyridin-2-amine (100 mg,0.50 mmol) in DMF (5 mL) was added NaH (60% in mineral oil) (40 mg, 1.0mmol) in portions and the mixture was stirred at room temperature for 1h to give solution B. Then the solid A was added to solution B and theresulting mixture continue to stir at room temperature for 1 h. Afterthe reaction was completed according to LCMS, the mixture was pouredinto water (20 mL). The precipitate was collected by filtered andconcentrated to dryness to give 206-E (80 mg, 42%) as a yellow solid.

Synthesis of 206. A mixture of 206-E (80 mg, 0.21 mmol) and Pd/C (80 mg)in MeOH (3 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified Pre-TLC(DCM:MeOH=10:1) to give 206 (25 mg, 34%) as a white solid.

Compound 208 was synthesized in a similar manner using the appropriatelysubstituted acid variant of 206.

Compound 208. 28 mg, 38%, a light yellow solid.

Compound 219 was synthesized in a similar manner usingpyridin-3-ylboronic acid and the appropriately substituted acid variantof 206.

Compound 219. 10 mg, 8%, a yellow solid.

Compound 226 was synthesized in a similar manner using4-fluorophenylboronic acid and the appropriately substituted acidvariant of 206.

Compound 226. 60 mg, 44%, a yellow solid.

Example 32. Synthesis of Compound 243

Synthesis of 243-A. A mixture of tert-butyl3-bromo-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (820 mg, 2.75 mmol),potassium acetate (540 mg, 5.5 mmol), dppf (111 mg, 0.08 mmol) andpalladium acetate (8.5 mg, 0.03 mmol) in ethanol (20 mL) was stirred at100° C. for 12 h under CO atmosphere at 1.5 MPa. The reaction mixturewas cooled to room temperature and filtered through Celite. The filtratewas concentrated in vacuo and the residue was dissolved with DCM (50mL), washed with brine (10 mL×3), dried over anhydrous Na₂SO₄ and thenconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (PE:EtOAc=8:1˜3:1) to give 243-A (670 mg, 84%) as a whitesolid.

Synthesis of 243-B. A mixture of 243-A (500 mg, 1.7 mmol) and NaBH₄ (390mg, 10.2 mmol) in ethanol (50 mL) was stirred at room temperature for 12h. The reaction mixture was concentrated in vacuo and and the residuewas dissolved with DCM (50 mL), washed with brine (10 mL×3), dried overanhydrous Na₂SO₄ and then concentrated in vacuo. The residue waspurified by column chromatography on silica gel (DCM:MeOH=100:1˜20:1) togive 243-B (350 mg, 81%) as a white solid.

Synthesis of 243-C. To a mixture of 243-B (150 mg, 0.6 mmol) in THF (5mL) was added NaH (60% in mineral oil) (96 mg, 2.4 mmol) at roomtemperature. The resulting mixture was stirred at room temperature for30 min. Then MeI (170 mg, 1.2 mmol) was added into above mixturedropwise. The resulting mixture was stirred at room temperature for 30min. The solution was diluted with water (10 mL), extracted with EtOAc(10 mL×3). The combined organic layer was washed with brine (10 mL×3),dried over anhydrous Na₂SO₄ and then concentrated in vacuo. The residuewas purified by column chromatography on silica gel (PE:EtOAc=8:1˜3:1)to give 243-C (60 mg, 38%) as a yellow solid

Synthesis of 243-D. To a solution of 243-C (60 mg, 0.23 mmol) in DCM (4mL) was added TFA (2 mL) dropwise at ice bath. Then the solution wasstirred at room temperature 1 h. The solvent was removed in vacuo togive 243-d as a crude product.

Synthesis of 243-E. A mixture of 243-D (0.23 mmol, crude product fromlast step), 143-C (80 mg, 0.17 mmol) and Na₂CO₃ (122 mg, 1.15 mmol) inacetonitrile was stirred at 50° C. for 3 h. After the reaction wascompleted according to LCMS. Na₂CO₃ was removed by filtration, thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography on silica gel (DCM:MeOH=100: 1-50:1) to give 243-E (70mg, 73%) as a yellow solid.

Synthesis of 243. A mixture of 243-E (70 mg, 0.16 mmol) and Pd/C (70 mg)in MeOH (5 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by filtration through the celite. Thefiltrate was concentrated and the residue was purified by pre-TLC(DCM:MeOH=15:1) to give 243 (48 mg, 78%) as a yellow solid

Example 33. Synthesis of Compound 224 and 225

Synthesis of 244-A. To a solution of tert-butyl4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate (1.40 g, 6.70 mmol)in DCM (10 mL) was added TFA (3 mL) dropwise under ice bath. Then thesolution was stirred at room temperature 1 h. The solvent was removed invacuo to give 244-A as a crude product.

Synthesis of 244-B. A mixture of 244-A (crude product from last step)and 143-C (1.58 g, 3.35 mmol) in acetonitrile (30 mL) was stirred at 50°C. for 30 min, then Na₂CO₃ (3.55 g, 33.5 mmol) was added into abovemixture and stirred at 50° C. for 1 h. The mixture was cooled to roomtemperature. Na₂CO₃ was removed by filtered, the filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (DCM:MeOH=100:1˜50:1) to give 244-B (0.98 g, 78%) as ayellow solid.

Synthesis of 244-C and 245-C. To a solution of 244-B (250 mg, 0.68 mmol)in DMF (5 mL) was added NaH (60% in mineral oil)(54 mg, 1.36 mmol) underice bath and stirred at room temperature for 30 min. Then SM-A (204 mg,0.82 mmol) was added into above mixture and stirred at for roomtemperature for 2 h. The mixture was quenched with water (15 mL),extracted with EtOAc (10 mL×3). The combined organic layer was washedwith brine (10 mL×3), dried over anhydrous Na₂SO₄ and then concentratedin vacuo. The residue was purified by column chromatography on silicagel (DCM:MeOH=100:1˜30:1) to give 244-C and 245-C (300 mg, 82%) as ayellow solid.

Synthesis of 244-D and 245-D. To a solution of 244-C and 245-C (300 mg,0.56 mmol) in DCM (3 mL) was added TFA (1 mL) dropwise under ice bath.Then the solution was stirred at room temperature 1 h. The solvent wasremoved in vacuo to give 244-D and 245-D as a crude product.

Synthesis of 244-E and 245-E. A mixture of 244-D and 245-D (crudeproduct from last step), formaldehyde solution (37% w/w, 0.6 mL) andacetic acid (2 drops) in MeOH (6 mL) was stirred at 40° C. for 1 h, thenNaBH(OAc)₃ (1.80 g, 8.48 mmol) was added into above solution. Thereaction mixture was stirred at 40° C. for 16 h. The solution was cooledto room temperature. The solution was diluted with water (10 mL),extracted with EtOAc (10 mL×3). The combined organic layer was washedwith brine (10 mL×3), dried over anhydrous Na₂SO₄ and then concentratedin vacuo. The residue was purified by column chromatography on silicagel (DCM:MeOH=200:1) to give 244-E (30 mg, 12% (two step)) as a yellowsolid and 245-E (90 mg, 36% (two step)) as a yellow solid.

Synthesis of 244. A mixture of 244-E (30 mg, 0.07 mmol) and Pd/C (30 mg)in MeOH (2 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified by Pre-TLC(DCM:MeOH=10:1) to give 244 (15 mg, 52%) as a yellow solid.

Synthesis of 245. A mixture of 245-E (90 mg, 0.20 mmol) and Pd/C (90 mg)in MeOH (6 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified by Pre-TLC(DCM:MeOH=10:1) to give 245 (50 mg, 59%) as a yellow solid.

Compounds 246 and 247 were synthesized in a similar manner using theappropriately substituted halogen variant of 244.

Compound 246. 20 mg, 54%, a yellow solid.

Compound 247. 6 mg, 43%, a yellow solid.

Example 34. Synthesis of Compound 257 and 258

Synthesis of 257-A and 258-A. A mixture of tert-butyl4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate (314 mg, 1.50 mmol),Cs₂CO₃ (978 mg, 3.00 mmol) and iodomethane (320 mg, 2.25 mmol) in DMF (6mL) was stirred at room temperature for 16 h. The mixture was dilutedwith water (18 mL), extracted with EtOAc (10 mL×3). The combined organiclayer was washed with brine (10 mL×3), dried over anhydrous Na₂SO₄ andthen concentrated in vacuo. The residue was purified by columnchromatography on silica gel (DCM:MeOH=100:1˜50:1) to give 257-A and258-A (270 mg, 81%) as a yellow solid.

Synthesis of 257-B and 258-B. To a solution of 257-A and 258-A (270 mg,1.21 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise under ice bath.Then the solution was stirred at room temperature 1 h. The solvent wasremoved in vacuo to give 257-B and 258-B as a crude product.

Synthesis of 257-C and 258-C. A mixture of 257-B and 258-B (crudeproduct from last step) and 143-C (286 mg, 0.61 mmol) in acetonitrile(10 mL) was stirred at 50° C. for 30 min, then Na₂CO₃ (581 mg, 6.05mmol) was added into above mixture and stirred at 50° C. for 1 h. Themixture was cooled to room temperature. Na₂CO₃ was removed by filtered,the filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (DCM:MeOH=200:1) to give 257-C (100mg, 44%) as a yellow solid and 258-C (50 mg, 22%) as a yellow solid.

Synthesis of 257. A mixture of 257-C (100 mg, 0.26 mmol) and Pd/C (100mg) in MeOH (5 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified by Pre-TLC(DCM:MeOH=15:1) to give 257 (50 mg, 55%) as a yellow solid.

Synthesis of 258. A mixture of 258-C (50 mg, 0.13 mmol) and Pd/C (50 mg)in MeOH (3 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by filtration through the celite. Thefiltrate was concentrated and the residue was purified by Pre-TLC(DCM:MeOH=15:1) to give 258 (25 mg, 55%) as a yellow solid.

Example 35. Synthesis of Compound 271

Synthesis of 127-A. A mixture of tert-butyl3-bromo-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (820 mg, 2.75 mmol),potassium acetate (540 mg, 5.5 mmol), dppf (111 mg, 0.08 mmol) andpalladium acetate (8.5 mg, 0.03 mmol) in ethanol (20 mL) was stirred at100° C. for 12 h under CO atmosphere at 1.5 MPa. The reaction mixturewas cooled to room temperature and filtered through Celite. The filtratewas concentrated in vacuo and the residue was dissolved with DCM (50mL), washed with brine (10 mL×3), dried over anhydrous Na₂SO₄ and thenconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (PE:EtOAc=8:1˜3:1) to give 127-A (670 mg, 84%) as a whitesolid.

Synthesis of 127-B. A mixture of 127-A (500 mg, 1.7 mmol) and NaBH₄ (390mg, 10.2 mmol) in ethanol (50 mL) was stirred at room temperature for 12h. The reaction mixture was concentrated in vacuo and and the residuewas dissolved with DCM (50 mL), washed with brine (10 mL×3), dried overanhydrous Na₂SO₄ and then concentrated in vacuo. The residue waspurified by column chromatography on silica gel (DCM:MeOH=100:1˜20:1) togive 127-B (350 mg, 81%) as a white solid.

Synthesis of 127-C. To a mixture of 127-B (150 mg, 0.6 mmol) and TEA(121 mg, 1.2 mmol) in DCM (10 mL) was added MsCl (104 mg, 0.9 mmol)dropwise and the mixture was stirred at room temperature for 1 h. Thesolution was diluted with DCM (20 mL) and the solution was washed withbrine (10 mL×3), dried over anhydrous Na₂SO₄ and then concentrated invacuo to give 127-C as crude product used to next step directly.

Synthesis of 127-D. A mixture of 127-C (crude product from last step),3-fluoroazetidine (59 mg, 0.78 mmol), K₂CO₃ (166 mg, 1.2 mmol) inacetonitrile (5 mL) was heated to 40° C. for 12 h. The solvent wasremoved in vacuo. The residue was dissolved with DCM (100 mL) and thesolution was washed with brine (30 mL×3). The organic layer was driedover anhydrous Na₂SO₄ and then concentrated in vacuo to give 127-D (150mg, 81%) as a yellow solid.

Synthesis of 127-E. To a solution of 127-D (150 mg, 0.49 mmol) in DCM (4mL) was added TFA (2 mL) dropwise at ice bath. Then the solution wasstirred at room temperature 1 h. The solvent was removed in vacuo togive 271-E as a crude product used to next step directly.

Synthesis of 127-F. A mixture of 127-E (crude product from last step),143-C (118 mg, 0.25 mmol) and Na₂CO₃ (212 mg, 2.0 mmol) in acetonitrilewas stirred at 50° C. for 3 h. After the reaction was completedaccording to LCMS. Na₂CO₃ was removed by filtration, the filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (DCM:MeOH=100:1˜50:1) to give 127-F (100 mg, 86%) as ayellow solid.

Synthesis of 127. A mixture of 127-F (100 mg, 0.14 mmol) and Ni (100 mg)in MeOH (5 mL) was stirred at room temperature for 1 h under H₂atmosphere. Ni was then removed by filtration through the Celite. Thefiltrate was concentrated and the residue was purified by Pre-TLC(DCM:MeOH=15:1) to give 271 (16 mg, 17%) as a yellow solid.

Example 36. Synthesis of Compound 351

Synthesis of 351-A. To a solution of 4-nitro-1H-pyrazole-3-carboxylicacid (8.00 g, 50.1 mmol) in MeOH (160 mL) cooled in an ice bath wasadded SOCl₂ (11.92 g, 100.2 mmol) dropwise. The reaction mixture wasslowly allowed to warm to room temperature and was stirred overnight.The MeOH and SOCl₂ were then distilled off and the residue was quenchedwith ice-water (50 mL). The product was extracted with DCM (100 mL×3).The organic layer was dried over anhydrous Na₂SO₄ and then concentratedin vacuo. The residue was triturated with diethyl ether (100 mL) to give351-A (8.70 g, 84%) as an off white solid.

Synthesis of 351-B. A mixture of 351-A (6.10 g, 29.4 mmol),4-fluorophenylboronic acid (5.43 g, 38.8 mmol), pyridine (9.29 g, 117.6mmol) and copper (II) acetate (8.03 g, 44.1 mmol) in DCM (120 mL) wasstirred at room temperature under air for 48 h. The residue was dilutedwith DCM (100 mL) and the solution was washed with brine (40 mL×3). Theorganic layer was dried over anhydrous Na₂SO₄ and then concentrated invacuo. The residue was purified by column chromatography on silica gel(PE:EtOAc=50:1˜10:1) to give 351-B (4.80 g, 62%) as an off white solid.

Synthesis of 351-C. A mixture of 351-B (4.80 g, 18.1 mmol) and KOH (1.01g, 18.1 mmol) in THF/H₂O (35 mL/15 mL) was stirred at room temperatureovernight. The THF was removed in vacuo. The aqueous layer adjusted topH=3 with diluted HCl solution. The precipitate was collected byfiltration and dried to give 351-C (4.00 g, 88%) as a white solid.

Synthesis of 351-D. A mixture of 351-C (3.50 g, 15.0 mmol), DPPA (7.65g, 27.8 mmol) and TEA (7.02 g, 69.5 mmol) in t-BuOH (50 mL) was heatedto reflux overnight under N₂ atmosphere. The solvent was removed invacuo. The residue was dissolved with EtOAc (100 mL) and the solutionwas washed with brine (40 mL×3). The organic layer was dried overanhydrous Na₂SO₄ and then concentrated in vacuon. The residue waspurified by column chromatography on silica gel (PE:EtOAc=70:30˜50:50)to give 351-D (2 g, 44%) as a yellow solid.

Synthesis of 351-E. To a solution of 351-D (2 g, 6.58 mmol) in DCM (14mL) was added TFA (7 mL) drop wise under ice bath. Then the solution wasstirred at room temperature 3 h. The solvent was removed in vacuo. Theresidue was dissolved with DCM (20 mL) and then adjusted to pH>10 byNaOH (1 N) solution. The mixture was extracted with DCM (50 mL×3). Thecombined organic layer was washed with brine (50 mL×3), dried overanhydrous Na₂SO₄ and then concentrated in vacuo. The residue waspurified by column chromatography on silica gel (DCM:MeOH=100:1˜30:1) togive 351-E (1.2 g, 80%) as a yellow solid.

Synthesis of 351-F. To a cooled (0° C.) suspension of NaH (118 mg, 50%in mineral oil, 2.45 mmol) in DMF (2 mL) was added 351-E (200 mg, 0.98mmol) and stirred for 10 minutes. Diphenyl carbonate (385 mg, 1.96 mmol)was added to the mixture and stirred with slow warming to roomtemperature for 1 h. AM351 (312 mg, 1.47 mmol) was added at 0° C. andstirred with slow warming to room temperature for 1 h. The reactionmixture was quenched with cold water (10 mL) and extracted with DCM (20mL×3). The combined organic layer was dried over anhydrous Na₂SO₄ andthen concentrated in vacuo. The residue was purified by columnchromatography on silica gel (DCM:MeOH=100:1. 25:1) to give 351-F (150mg, 38%) as a brown solid.

Synthesis of 351. A mixture of 351-F (150 mg, 0.37 mmol) and Pd/C (35mg) in MeOH (5 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by filtration through the celite. Thefiltrate was concentrated and the residue was purified by Prep-HPLC togive 351 (45 mg, 32%) as an off white solid.

Compounds 352, 353, 360, 361, 382, 383 and 384 were synthesized in asimilar manner using the appropriately substituted amine variant of 351.

Compound 352. 20 mg, 28%, an off white solid.

Compound 353.17 mg, 20%, an off white solid.

Compound 360. 31 mg, 34%, a brownish solid.

Compound 361. 35 mg, 37%, a white solid.

Compound 382. 15 mg, 14%, an off white solid.

Compound 383. 12 mg, 13%, an off white solid.

Compound 384. 25 mg, 21%, an off white solid.

Example 37. Synthesis of Compound 364

Synthesis of 364-A. To a degassed mixture of 2-Amino-6-chloro-3-nitropyridine (5 g, 28.80 mmol), 4-fluorophenyl boronic acid (8.06 g, 57.61mmol) and Cs₂CO₃ (23.89 g, 72.02 mmol) in 1,4-dioxane (50 mL) and water(15 mL) was added Pd(PPh₃)₂Cl₂ (0.5 g, 0.72 mmol) and the mixture wasstirred at 100° C. overnight. The reaction mixture was concentrated invacuum. The residue was dissolved with ethyl acetate (100 mL) and thesolution was washed with brine (50 mL×3). The organic layer was driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (PE:EtOAc=75:25˜70:30)to give 364-A (4.8 g, 71.53%) as a yellow sold.

Synthesis of 364-B. To a cooled (0° C.) suspension of NaH (82 mg, 50% inmineral oil, 1.71 mmol) in DMF (2 mL) was added 364-A (200 mg, 0.85mmol) and stirred for 10 minutes. Diphenyl carbonate (458 mg, 2.14 mmol)was added to the mixture and stirred with slow warming to roomtemperature for 1 h. 3,3-difluoropyrrolidine (137.71 mg, 1.28 mmol) wasadded at 0° C. and stirred with slow warming to room temperature for 1h. The reaction mixture quenched with cold water (10 mL) and extractedwith DCM (20 mL×3). The combined organic layer was dried over anhydrousNa₂SO₄ and then concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (DCM:MeOH=100: 1-25:1) to give 364-B(150 mg, 47%) as a yellow solid.

Synthesis of 364. A mixture of 364-B (140 mg, 0.38 mmol) and Pd/C (35mg) in MeOH (5 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by filtration through the celite. Thefiltrate was concentrated and the residue was purified by Prep-HPLC togive 364 (70 mg, 54%) as a pale yellow solid.

Compounds 362, 363, 365, 367, 371, 372, 373, 374, 385, 386, 387, 388,389, 390, 392, 396 and 397 were synthesized in a similar manner usingthe appropriately substituted boronic acid and amine variant of 364.

Compound 362. 15 mg, 18%, an off white solid.

Compound 363. 68 mg, 34%, an off white solid.

Compound 365. 30 mg, 54%, an off white solid.

Compound 367. 52 mg, 55%, an off white solid.

Compound 371. 47 mg, 45%, an off white solid.

Compound 372. 45 mg, 38%, an off white solid.

Compound 373. 42 mg, 38%, an off white solid.

Compound 374. 48 mg, 34%, an off white solid.

Compound 385. 80 mg, 44%, an off white solid.

Compound 386. 130 mg, 76%, an off white solid.

Compound 387. 15 mg, 19%, an off white solid.

Compound 388. 60 mg, 33%, an off white solid.

Compound 389. 168 mg, 73%, an off white solid.

Compound 390. 80 mg, 43%, an off white solid.

Compound 392. 70 mg, 38%, an off white solid.

Compound 396. 85 mg, 56%, a pale yellow solid.

Compound 397. 27 mg, 27%, a pale yellow solid.

Compound 398. 110 mg, 46%, a yellowish solid.

Compound 399. 100 mg, 46%, an off white solid.

Compound 400. 32 mg, 34%, an off white solid.

Compound 401. 8 mg, 06%, an off white solid.

Compound 403. 145 mg, 78%, an off white solid.

Compound 404. 165 mg, 91%, an off white solid.

Compound 405. 64 mg, 46%, an off white solid.

Compound 408. 45 mg, 43%, an off white solid.

Compound 409. 15 mg, 18%, an off white solid.

Compound 410. 33 mg, 30%, an off white solid.

Compound 411. 100 mg, 63%, an off white solid.

Example 38. Synthesis of Compound 381

Synthesis of 381-A. To a cooled (0° C.) solution of N-bocpiperidine-4-carboxylic acid (1 g, 4.36 mmol) in DCM (10 mL) was addedCDI (0.84 gm, 5.23 mmol) and the reaction mixture was stirred at 0-4° C.for 8 h. The reaction mixture was diluted with diethyl ether (50 mL) andwashed with water (20 mL), NaHCO₃ (10 mL, 10% in water) and brine (10mL). The organic layer was dried over anhydrous Na₂SO₄ and concentratedin vacuo to get 381-A (1 g, 70%) as a white solid.

Synthesis of 381-B. To a cooled (0° C.) suspension of NaH (222 mg, 50%in mineral oil, 4.62 mmol) in DMF (5 mL) was added 364-A (0.5 g, 2.31mmol) and stirred for 20 minutes. 381-A (0.37 g, 2.31 mmol) was added tothe mixture and stirred with slow warming to room temperature for 2 h.Then the reaction mixture was quenched with cold water (25 mL) andextracted with DCM (25 mL×3). The combined organic layer was dried overanhydrous Na₂SO₄ and then concentrated in vacuo. The residue waspurified by column chromatography on silica gel (DCM:MeOH=100:1-50:1) togive 381-B (0.7 g, 71%) as a yellow solid.

Synthesis of 381-C. To a cooled (0° C.) solution of 381-B (0.5 g, 1.17mmol) in DCM (10 mL) was added TFA (1 mL). The reaction mixture wasstirred at room temperature overnight. Then the reaction mixture wasconcentrated in vacuo. The residue was triturated with diethyl ether togive 381-C. TFA (0.35 g, 68%) as a yellow solid.

Synthesis of 381-D. To a solution of 381-C. TFA (0.3 g, 0.92 mmol) andoxetan-3-one (0.36 g, 5.05 mmol) in DCM (7.5 mL) and MeOH (2.5 mL) wasadded AcOH (5.5 mg, 0.09 mmol) and stirred at room temperature for 4 h.NaBH₃CN (0.17 g, 2.85 mmol) was added at 0° C. and stirred at roomtemperature overnight. The reaction mixture was quenched with water (15mL) and extracted with DCM (25 mL×3). The combined organic layer wasdried over anhydrous Na₂SO₄ and then concentrated in vacuo. The residuewas purified by column chromatography on silica gel(DCM:MeOH=100:10-50:5) to give 381-D (200 mg, 57%) as a yellow solid.

Synthesis of 381. A mixture of 381-D (150 mg, 0.39 mmol) and Pd/C (35mg) in MeOH (5 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by filtration through the celite. Thefiltrate was concentrated and the residue was purified by Prep-HPLC togive 381 (45 mg, 34%) as a brown gum.

Compounds 368, 377, 378 and 379 were synthesized in a similar mannerusing the appropriately substituted 364-A and carbonyl compound variantof 381.

Compound 368. 35 mg, 47%, an off white solid.

Compound 377. 45 mg, 35%, an off white solid.

Compound 378. 75 mg, 20%, an off white solid.

Compound 379. 75 mg, 53%, an off white solid.

Example 39. Synthesis of Compound 357

Compound 357-C was synthesized in a similar manner using 364-A variantof 381-C.

Synthesis of 357. A mixture of 357-C (150 mg, 0.48 mmol) and Pd/C (35mg) in MeOH (5 mL) was stirred at room temperature for 1 h under H₂atmosphere. Pd/C was then removed by filtration through the celite. Thefiltrate was concentrated and the residue was purified by Prep-HPLC togive 357 (20 mg, 15%) as an off white solid.

Example 40. Synthesis of Compound 354

Compound 357-A (140 mg, 67%, as a yellow solid) was synthesized in asimilar procedure used for 381-D from 381-C.

Compound 354 (35 mg, 38%, as an off white solid) was synthesized in asimilar procedure used for 357 from 357-C.

Example 41. Synthesis of Compound 358

Synthesis of 358-A. To a solution of 357-C (150 mg, 0.48 mmol) and TEA(144 mg, 1.42 mmol) in DCM (10 ml) was added Ac₂O (48 mg, 0.48 mmol) andthe mixture was stirred at room temperature for 4 h. The reactionmixture was quenched with water (10 ml) and extracted with DCM (20mL×3). The combined organic layer was dried over anhydrous Na₂SO₄ andthen concentrated in vacuo. The residue was purified by columnchromatography on silica gel (DCM:MeOH=100:1-50:1) to give 358-A (100mg, 58%) as a yellow solid.

Compound 358 (40 mg, 44%, as a brown solid) was synthesized in a similarprocedure used for 357 from 357-C.

Example 42. Synthesis of Compound 359

Compound 359-A (75 mg, 63%, as a brown solid) was synthesized in asimilar procedure used for 381-D from 381-C.

Compound 379 (15 mg, 23%, as a brownish solid) was synthesized in asimilar procedure used for 357 from 357-C.

Example 43. Synthesis of Compound 375

Compound 375-A (500 mg, 40%, as a yellow solid) was synthesized in asimilar procedure used for 364-A.

Compound 375-B (100 mg, 29%, as a yellow semi-solid) was synthesized ina similar manner using (1-methylpiperidine-4-yl) methanol instead ofamine for 364-B.

Compound 375 (10 mg, 11%, as a colorless semi-solid) was synthesized ina similar procedure used for 364 from 364-B.

Example 44. Synthesis of Compound 366

Compounds 366-A (100 mg, 30%, a yellow solid) was synthesized in asimilar manner using the appropriately substituted amine variant of364-B.

Synthesis of 366. To a cooled (0° C.) solution of 366-A in THF (5 mL)was added a solution of LAH in THF under nitrogen and the mixture wasstirred with slow warming to 10° C. for 2 h. The reaction mixture wasquenched with saturated aqueous solution of Na₂SO₄. The solid wasfiltered, washed with DCM (20 ml). The combined filtrate was dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bypreparative HPLC to give 366 (10 mg, 11%) as an off white solid.

Compounds 350 and 395 were synthesized in a similar manner using theappropriately substituted ortho nitro amine and boronic acid variant of366.

Compound 350. 13 mg, 14%, an off white solid.

Compound 395. 10 mg, 11%, a greenish solid.

Example 45. Synthesis of Compound 394

Synthesis of 394-A. A mixture of 396-A (130 mg, 0.32 mmol) and MnO₂ (250mg, 3.2 mmol) in DCM (10 mL) was stirred at room temperature overnight.The MnO₂ was then removed by filtration through the celite. The filtratewas concentrated to give 394-A (125 mg, 96%) as an yellowish solid.

Synthesis of 394-B. To a cooled (−78° C.) solution of 394-A (115 mg,0.28 mmol) in THF was added a solution of MeMgBr (0.37 mL, 3M in THF,1.12 mmol) under nitrogen and the mixture was stirred with slow warmingto room temperature overnight. The reaction mixture was quenched withsaturated Na₂SO₄ solution. The solid was filtered, washed with DCM (20mL). The organic part was concentrated in vacuo. The residue waspurified by column chromatography on silica gel (DCM:MeOH=100:1-100:5)to give 394-B (55 mg, 46%) as a yellow solid.

Compound 394 (10 mg, 20%, as an off white solid) was synthesized in asimilar procedure used for 364 from 364-B.

Example 46. Synthesis of Compound 369

Synthesis of 369-A. To a suspension of 2-amino-6-chloro-3-nitro pyridine(1 g, 5.7 mmol) and K₂CO₃ (1.99 g, 14.45 mmol) in acetonitrile (5 mL)was added 1H-pyrazole (579.05 mg, 8.64 mmol) the mixture was heated at70° C. overnight. K₂CO₃ was then removed by filtration through thecelite. The filtrate was concentrated and the residue was purified bytrituration with diethyl ether to give 369-A (800 mg, 67%) as a yellowsolid.

Compound 369-B (110 mg, 43%, as a yellow solid) was synthesized in asimilar procedure used for 364-B from 364-A.

Compound 369 (43 mg, 47%, as an off white solid) was synthesized in asimilar procedure used for 364 from 364-B.

Example 47. Synthesis of Compound 391

Compound 391-A (200 mg, 45%, as a yellow solid) was synthesized in asimilar manner with amine variant of 364-B.

Synthesis of 391-B. To a degassed mixture of 391-A (200 mg, 0.48 mmol),1-methylpiperazine (58 mg, 0.58 mmol), Xanthphos (14 mg, 0.024 mmol) andNaOBu^(t) (80 mg, 0.72 mmol) in toluene (10 mL) was added Pd₂(dba)₃ (22mg, 0.024 mmol) under N₂ and the mixture was stirred at 100° C.overnight. The reaction mixture was concentrated in vacuo. The residuewas dissolved in ethyl acetate (50 mL) and washed with brine (30 mL).The organic layer was dried over anhydrous Na₂SO₄ and concentrated invacuum. The residue was purified by column chromatography on silica gel(MeOH:CHCl3=100:1-100:5) to give 391-B (100 mg, 43%) as a yellow solid.

Compound 391 (15 mg, 16%, as an off white solid) was synthesized in asimilar procedure used for 364 from 364-B.

Example 48. Synthesis of AM351

Synthesis of AM351-A. A degassed mixture of tert-butyl5-bromoisoindoline-2-carboxylate (5.0 g, 16.76 mmol), Pd(OAc)₂ (564 mg,2.51 mmol), DPPP (1.38 g, 3.35 mmol) and TEA (5.08 g, 50.30 mmol) in amixture of MeOH (30 mL) and DMSO (30 mL) was heated at 80° C. undercarbon monoxide atmosphere overnight. Pd(OAc)₂ was then removed byfiltration through the celite. The filtrate was concentrated in vacuoand the residue was purified by column chromatography on silica gel(PE:EtOAc=75:25˜70:30) to get AM351-A (2.5 g, 53%) as an off whitesolid.

Synthesis of AM351-B. To a cooled (0° C.) solution of AM351-A (2 g, 7.17mmol) in THF (20 mL) was added a solution of LAH in THF (10.8 mL, 1M inTHF, 10.8 mmol) under nitrogen and the mixture was stirred with slowwarming to 10° C. for 2 h. The reaction mixture was quenched withsaturated aqueous solution of Na₂SO₄. The solid was filtered, washedwith DCM (100 mL). The combined filtrate was dried over anhydrous Na₂SO₄and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (PE:EtOAc=50:50˜40:60) to get AM351-B (1.5g, 80%) as a white solid.

Synthesis of AM351-C. To a mixture of AM351-B (0.8 g, 3.21 mmol) andPPh3 (1.26 g, 4.82 mmol) in dichloromethane was added CBr₄ (1.59 g, 4.82mmol) and the mixture was stirred at rt for 4 h. Then the mixture wasconcentrated and the crude was purified by column chromatography onsilica gel (PE:EtOAc=80:20˜70:30) to get AM351-C (570 mg, 57%) as awhite solid.

Synthesis of AM351-D. To a mixture of AM351-C (570 mg, 1.9 mmol) andK₂CO₃ (655 mg, 4.75 mmol) in THF (10 mL) was added dimethylamine.HCl(387 mg, 4.75 mmol) in portions. Then the mixture was stirred at roomtemperature for 4 h. K₂CO₃ was then removed by filtration through thecelite and washed with DCM (20 mL). The combined filtrate wasconcentrated in vacuo to give AM351-D (480 mg, 95%) as a yellowishsemi-solid.

Synthesis of AM351. To a cooled (0° C.) solution of AM351-D (480 mg,1.89 mmol) in DCM (5 mL) was added a solution of dry HCl in diethylether (10 mL, 2M) and the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo and theresidue was triturated with diethyl ether to give AM351 (350 mg, 95%) asa purple solid.

Compounds AM353, AM355, AM363, AM386, AM408 and AM410 were synthesizedin a similar manner using the appropriately substituted amine variant ofAM351.

Compound AM353. 210 mg, 87%, a grey solid.

Compound AM355. 300 mg, 93%, a light pink solid.

Compound AM363. 300 mg, 94%, an off white solid.

Compound AM386. 300 mg, 92%, an off white solid.

Compound AM408. 210 mg, 84%, a grey solid.

Compound AM410. 210 mg, 89%, a grey solid.

Compound AM411 (200 mg, 84%, a white solid) was synthesized in a similarmanner using appropriate starting material and amine variant of AM351.

Example 49. Synthesis of AM362

Synthesis of AM362-A. To a degassed mixture of tert-butyl5-bromoisoindoline-2-carboxylate (1 g, 3.3 mmol),1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.12g, 5.031 mmol) and Cs₂CO₃ (3.2 g, 9.9 mmol) in 1,4-dioxane (10 mL) wasadded Pd(dppf)Cl₂ under N₂ atmosphere and the mixture was heated at 95°C. overnight. The reaction mixture was diluted with DCM (25 mL) and thecatalyst was removed by filtration through the celite. The filtrate wasconcentrated in vacuo and the residue was purified by columnchromatography on silica gel (PE:EtOAc=80:20˜60:40) to give AM362-A (0.8g, 76%) as a brown gum.

Compound AM362 (450 mg, 95%, a brown solid) was synthesized in a similarprocedure used for AM351 from AM351-D.

Compound AM403 (250 mg, 96%, a yellow solid) was synthesized in asimilar manner using the appropriately substituted boronic acid pinacolester variant of AM362.

Example 50. Synthesis of AM393

Synthesis of AM393-A. To a cooled (0° C.) solution of NaH (190 mg, 50%in mineral oil, 4.0 mmol) in DMF (5 mL) was added AM351-A (400 mg, 1.6mmol) and the mixture was stirred at room temperature for 20 min. Thereaction mixture was cooled to 0° C. and methyl iodide was added. Thereaction mixture was stirred with slow warming to room temperature for 1h. The reaction mixture was quenched with ice-cold water (10 mL) and theproduct was extracted with DCM (20 mL×3). The combined organic layer waswashed with brine (20 mL) and dried over anhydrous Na₂SO₄. The solventwas removed in vacuo and the residue was purified by columnchromatography on silica gel (PE:EtOAc=90:10˜85:15) to give AM393-A (360mg, 85%) as a yellowish gum.

Compound AM393 (120 mg, 99%, a grey solid) was synthesized in a similarprocedure used for AM351 from AM351-D.

Example 51. Synthesis of AM374

Synthesis of AM374-A. To a degassed mixture of tert-butyl5-bromoisoindoline-2-carboxylate (1 g, 3.35 mmol), 1-methylpiperazine(403 mg, 4.03 mmol), Xanthphos (97 mg, 0.17 mmol) and NaOBu^(t) (482 mg,5.03 mmol) in toluene (10 mL) was added Pd₂(dba)₃ (153 mg, 0.17 mmol)under N₂ and the mixture was stirred at 100° C. overnight. The reactionmixture was concentrated in vacuo. The residue was dissolved in ethylacetate (50 mL) and washed with brine (30 mL). The organic layer wasdried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (MeOH:CHCl₃=99:1˜95:5)to give AM374-A (800 mg, 75%) as a white solid.

Compound AM374 (510 mg, 93%, an off white solid) was synthesized in asimilar procedure used for AM351 from AM351-D.

Example 52. Synthesis of AM398

Synthesis of AM398-A. To a degassed solution of tert-butyl5-bromoisoindoline-2-carboxylate (1.0 g, 3.35 mmol) in DMF (10 mL) wereadded tri-n-butyl(1-ethoxyvinyl) stannane (1.33 g, 3.69 mmol) andPd(PPh₃)₂Cl₂ (117 mg, 0.16 mmol) and the mixture was heated at 130° C.in Microwave for 2 h. The reaction mixture was concentrated in vacuo.The residue was dissolved with ethyl acetate (50 mL) and washed withbrine (30 mL). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (PE:EtOAc=75:25˜70:30) to give AM398-A (400 mg, 46%) as ayellow sold.

Synthesis of AM398-B. To a solution of AM398-A (400 mg, 1.53 mmol) inTHF (10 mL) were added pyrrolidine (435 mg, 6.13 mmol) andTi(IV)isoproxide (1.39 g, 6.13 mmol) and the mixture was stirred at roomtemperature overnight. EtOH (5 mL) was added to the reaction mixture andcooled to 0° C. NaBH4 (232 mg, 6.13 mmol) was added in portions and themixture was stirred at room temperature for 30 min. Then the reactionmixture was quenched with ice-cold water (10 mL) and extracted withethyl acetate (50 mL×3). The organic layer was washed with brine (30mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas purified by column chromatography on silica gel(PE:EtOAc=60:40˜50:50) to give AM398-B (300 mg, 62%) as a pale yellowliquid.

Compound AM398 (210 mg, 87%, a yellowish solid) was synthesized in asimilar procedure used for AM351 from AM351-D.

Example 53. Reporter Displacement Assay

HDAC2 containing a C-terminal HIS-Tag (Proteros) andfluorescently-labeled anti-HIS-antibody are diluted in one vial in assaybuffer 50 mM Tris, pH 8.0, 1 mM DTT, 150 mM NaCl, and 0.01% Tween20.Components are pre-incubated for 30 min, then a small volume of reporterprobe (Proteros) is added from a highly concentrated stock andincubation is continued for another 30 min. Final concentrations afteradding the reporter probe amount to 20 nM HDAC2, 4 nM antibody, and 180nM probe.

Ten μl/well of pre-formed complex are transferred into 384 well assayplates (Corning). Compounds to be profiled are serially diluted from1×10¹-5.7×10⁵ mM in DMSO and 60 nl are added to assay plates by pintooltransfer (CybiWell, Cybio). Fluorescence intensity signal is read after4 hours in a Pherastar FS (BMG Labtech) at 337/665 nm.

For K_(d) determination, percent probe displacement values arecalculated for each compound concentration and plotted against thecompound concentration. IC₅₀-like values (corresponding to 50% probedisplacement) are calculated using standard fitting algorithms. Sincethe reporter probe is used at a concentration reflecting its own K_(d)value, compound K_(d) values can be calculated according to the ChengPrusoff equation.

The results of this assay for compounds useful in this invention arereported in Table 4, below. In the table, “A” indicates a K_(d) value ofless than 0.1 μM; “B” a K_(d) value of between 0.1 μM and 0.5 μM; “C” aK_(d) value of greater than 0.5 μM and less than or equal to 5.0 μM; and“D” a K_(d) value of greater than 5.0 μM.

TABLE 4 HDAC1 and HDAC2 K_(d) Values for Exemplary Compounds Useful inthe Invention Patent HDAC2 HDAC1 Compound HDAC2 K_(d), residence HDAC1K_(d), residence No. (μM) time (min) (μM) time (min) 100 B 703 B 196 101D 0 D 0 102 D 0 D 0 103 D 0 D 0 104 D 0 D 0 105 C 634 C 851 106 D 0 D121 107 C 1278 C 653 108 C 1430 C 401 109 C 264 D 14 110 D 0 C 688 111 D540 D 151 112 B 790 B 329 113 B 609 A 350 114 D 0 D 49 115 C 185 D 0 116C 114 C 87 117 D 42 D 0 118 C 176 C 69 119 B 1198 B 126 120 C 1167 B 830121 D 1204 C 682 122 B 2376 B 572

Example 54. Enzymatic and Cell Assay

HDAC Enzymatic Assay

All recombinant human HDACs were purchased from BPS Bioscience. Thesubstrate, FAM-TSRHK(AC)KL-CONH, was synthesized at NanoSyn. Final assayreactions contained 100 mM HEPES (pH 7.5), 50 mM KCl, 0.1% BSA, 0.01%Triton X-100, 1% DMSO, 1 uM substrate and 5 nM HDAC enzyme. Enzyme andcompounds were pre-incubated at 25° C. for 5 hours and reactions wereinitiated by addition of substrate. 10 uL reactions were incubated for17 hours at 25° C. and terminated by the addition of 40 uL of buffercontaining 100 mM HEPES (pH 7.5), 0.1% BSA, 0.01% Triton X-100 and 0.05%SDS. Substrate and product peptides present in each sample wereseparated electrophoretically using the LabChip 3000 capillaryelectrophoresis instrument. Change in the relative fluorescenceintensity of the substrate and product peaks reflects enzyme activity.Reaction progress was determined as the product to sum ratio(PSR):P/(S+P), where P is the peak height of the product peptide and Sis the peak height of the substrate peptide. Reactions were performed induplicate at 12 concentrations, (3× serial dilutions starting at 30 uM).IC₅₀ values were calculated using a 4 Parameter Logistic Model.

Cell Culture and Inhibitor Treatments

SH-SY5Y cells (Sigma) were cultured in Eagle's Modified Essential Mediumsupplemented with 10% fetal bovine serum and pen/strep. Twenty-fourhours prior to compound dosing 20 uL of cells were plated in white 384well plates at a density of 1,500 cells/well. Compounds were seriallydiluted in neat DMSO and then diluted 1:100 v/v into media without FBSand mixed. Media was removed from the plated cells and the dilutedcompounds in serum free media (1% v/v final DMSO) were added andincubated at 37° C. for five hours. Ten uL of HDAC-Glo 2 reagent with0.1% Triton X-100 was then added, the plate was mixed and allowed todevelop at room temperature for 100 minutes. Plates were then read witha Spectramax LMax luminometer employing a 0.4 s integration time. Doseresponse curves were constructed with normalized data where CI-994 at100 uM was defined as 100% inhibition and DMSO alone as 0% inhibition.

TABLE 5 IC₅₀ and EC₅₀ Values for Exemplary Compounds Useful in theInvention Patent Patent Comound IC₅₀ EC₅₀ Compound IC₅₀ EC₅₀ No. (μM)(μM) No. (μM) (μM) 123 D 244 C 124 D 245 B 125 C 246 D 126 C 247 B 137 C248 C 143 C 249 D 144 B B 250 B B 145 B B 251 B B 146 B C 252 B B 147 B253 B B 148 B C 254 C 149 B B 255 B 150 B 256 C 151 B 257 B B 152 C 258C C 153 B 259 B 154 B B 260 B 155 B B 261 D 156 B B 262 D 157 B 263 C C158 B 264 D 159 B C 265 C C 160 B 266 C C 161 B B 267 D D 162 B B 268 DD 163 B B 269 D D 164 C 270 D D 165 B 271 C C 166 C 272 B B 167 D 273 BB 168 B 274 B B 169 C 275 B B 170 C 276 C C 171 D 277 C C 172 C 350 C173 C 351 B 174 D 352 C 175 D 353 C 176 C 354 D 177 D 356 D 178 D 357 D179 C 358 D 181 D 359 D 182 D 360 D 183 D 361 D 184 D 362 B 185 C 363 B186 C 364 C 187 C 365 B 188 C 366 B C 189 D 367 B C 190 D 368 C 191 C369 C 192 D 370 D 193 D 371 B C 194 D 372 C 195 D 373 B C 196 D 374 B197 D 375 D 198 D 376 D 199 D 377 D 201 D 378 D 203 D 379 D 204 D 380 D205 D 381 D 206 C 382 D 208 C 383 B 210 D 384 D 211 D 385 C 212 D 386 B214 C 387 C 215 D 388 C 218 D 389 D 219 D 390 C 220 D 391 B B 221 D 392C 222 D 393 C 223 D 394 B 224 D 395 D C 225 C 396 B 226 B 397 B B 228 C401 D 232 C 402 235 D 403 236 D 404 237 D 405 B B 238 C 406 D 239 D 407D 240 B 408 B 241 D 409 B 242 D 410 B 243 B C “A” indicates a IC₅₀ orEC₅₀ value of less than 0.1 μM; “B” an IC₅₀ or EC₅₀ value of between 0.1μM and 0.5 μM; “C” an IC₅₀ or EC₅₀ value of greater than 0.5 μM and lessthan or equal to 5.0 μM; and “D” an IC₅₀ or EC₅₀ value of greater than5.0 μM.

Morris Water Maze Task

The compounds described herein (e.g., compounds according to Formula I,II or any of Compounds 100-128 or any of those in Tables 2 or 3) can beexamined for its efficacy in the model behavior paradigm, the Morriswater maze task as described below:

The water maze task was originally designed by Morris et al. (J NeurosciMethods. 1984; 11: 7-60). Testing is performed in a large dark-coloredtank (200 cm in diameter) filled with clear water at a temperature of25.0±1.0° C. A submerged platform (square platform: 10×10 cm; 1.5 cmbelow water surface) is placed in the middle of the of the NW quadrant.The starting locations, which are labeled N, NE, E, SE, S, SW, W, NW,are located arbitrarily on the pool rim. The rats are lowered into thepool with their nose pointing toward the wall at one of the startingpoints. The release point adjacent to platform location (NW) is notused.

At first, before the compound treatment is started, the visible platformpre-training is performed to determine whether any non-cognitiveperformance impairments (e.g. visual impairments and/or swimmingdifficulties) are present, which might affect performance on the placeor probe trials. All rats receive 4 trials in one day with inter-trialinterval of 15 min. On each trial, rats are placed in a fixed positionin the swimming pool facing the wall and are allowed to swim to aplatform with a rod (cue) 20 cm above water level randomly placed inmiddle of the pool. They are allowed 60 s to find the platform, whichthey stay on for 15 s before being removed from the pool. If a rat doesnot find the platform within 60 s, the rat will be gently guided to theplatform and allowed to remain there for 15 s. The time for each rat toreach the cued platform, distance swam, thigmotaxis, and the swim speedare recorded. After the visible platform pre-training is completed, thedata is analyzed and the rats are assigned to the different treatmentgroups based on their pre-training performance. This procedure isperformed to ensure that each treatment group consist equally both goodand poor performers in the cued version of the water maze task.

Acquisition training—week 1: After completion of cued trials,acquisition (place) trials are executed to determine the rat's abilityto learn the spatial relationship between distant cues and the escapeplatform (submerged, no cue rod), which remain in the same location forall place trials. The starting points are randomized (NW is not used).The rats receive four trials (15 min apart, 60 s maximum for each trial)each day for 4 days. Latency, path length, thigmotaxis and swim speedare recorded.

Acquisition training—week 2: A second set of acquisition trials isexecuted to determine the rat's ability to learn the spatialrelationship between distant cues and the escape platform (submerged, nocue rod), which remain in the same location for all place trials. Thestarting points are randomized (NW is not used). The rats receive fourtrials (15 min apart, 60 s maximum for each trial) each day for 4 days.Latency, path length, thigmotaxis and swim speed are recorded.

Probe trial: A single probe trial is conducted 24 hours after the lastplace trials to evaluate memory retention capabilities. The platform isremoved from the water maze and rat is started to swim in the quadrantopposite to one the platform was placed before. The rats are allowed toswim for 60 s during the probe trial. During the probe trial, the timespent in target quadrant and target platform annulus (36-cm-diametercircular area surrounding platform), and crosses over the targetplatform position are measured (memory retention).

After completing the behavioral tests, the rats are sacrificed andtissue collected for further analysis. Blood was collected and processedto peripheral mononuclear cells and plasma. The cells can be furtherassayed for acetylation marks to demonstrate that compounds wereinhibiting HDAC2 activity. The plasma can be frozen and later assayed bymass spectrometry for the presence of compound. Brain can be collected,dissected into cerebellum and hippocampus. Cerebellum can be frozen andlater homogenized and the compound can be extracted and measured by massspectrometry.

Hippocampal brain tissue can be processed to extract RNA for geneexpression analysis. Tissue can be washed with phosphate buffered saline(PBS). RNA can be isolated using the RNeasy isolation kit (Qiagen)according to manufacturer's instructions. The RNA is eluted in 30 μlRNAse free water. The concentration of the isolated RNA can be measuredby nanodrop. The RNA can be converted into cDNA with the iScript kit(Biorad) according to manufacturer's instructions. 800 ng of RNA wasused per sample. After cDNA synthesis the DNA was diluted 1:5 withmilliQ water. Quantitative PCR was done with the SSo advanced supermix(Biorad). Reactions can be done in a white 96-well plate, each reactioncontained 1 μl template, 0.75 μl primer mix (forward & reverse, both at10 μM), 5.75 μl water and 7.5 μL SSo SYBR green advanced supermix.Detection can be done with a CFX Connect Instrument (Biorad).Gene-specific primers for the following genes can be used in thesestudies: GAPDH—glyceraldehyde-3-phosphate dehydrogenase: BDNF—BrainDerived Neurotrophic Factor: GRIN2A and GRIN2B Glutamate receptorN-methyl D-aspartate-associated proteins 1& 2: CDK5—cyclin-dependentkinase 5: HOMER1: GRIA1 and GRIA2—glutamate receptor, AMPA 1 & 2:EGR1—early growth response 1: NEFL—neurofilament, light polypeptide:SYT1—Synaptotagmin 1: SYP—synaptophysin. Values can be normalized toexpression levels of GAPDH. Three replicates of each sample can be runin each assay and the mean of the replicates can be compared forstatistical significant changes.

Peripheral blood mononuclear cells can be isolated using a Ficoll-PaquePlus (GE Healthcare) and can be tested for acetylation marks followingtreatment with HDCA2 inhibitors. Blood cells can be lysed and proteinscan be extracted using 13 RIPA buffer containing proteinase (complete,Roche) and phosphatase inhibitors (1 mMb-glycerophosphate, 10 mM NaF,0.1 mM Na3VO4) and then can be transferred onto PVDF membranes (Biorad)and stripped using stripping buffer (Thermo Scientific). The followingprimary antibodies can be used: acetyl-K (Cell Signaling) and actin(Sigma). Secondary antibodies were horseradish peroxidase-linked (GEHealthcare). Signal intensities can be quantified using Image J 1.42qand normalized to values of actin.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments, which utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments, which have been represented by way of example.

We claim:
 1. A compound having the formula:

or a pharmaceutically acceptable salt thereof.